Inhibitors of mlh1 and/or pms2 for cancer treatment

ABSTRACT

The present invention relates to compounds of Formula (I) that target the MLH1 and/or PMS2 proteins that are components of the DNA Mismatch Repair (MMR) process: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , R 6  and R 10  are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which MLH1 and/or PMS2 activity is implicated.

INTRODUCTION

The present invention relates to certain compounds that function asinhibitors of MLH1 and/or PMS2 protein activity. The compounds of thepresent invention may be used to treat disease or conditions mediated,at least in part, by inappropriate MLH1 and PMS2 activity, for example,cancer. The invention furthermore relates to the use of the compounds aspharmaceuticals, processes for making them and pharmaceuticalcompositions comprising them.

BACKGROUND OF THE INVENTION

Cancer is caused by altered cellular proliferation. Precisely whatcauses a cell to become malignant and proliferate in an uncontrolled andunregulated manner has been the focus of intense research over recentdecades. This research has led to the identification of moleculartargets associated with key pathways that enable such malignancies.

Mismatch repair (MMR) is a highly conserved DNA repair pathway thatplays a major role during DNA replication, repair and recombination, aswell as during meiosis in eukaryotes and immunoglobulinmaturation/diversification in mammals. MMR promotes genome stability inall organisms by correcting DNA base mismatches and insertion/deletion(indel) loops that can occasionally arise during normal DNA replicationprocess. Base pair mismatches occur when incorrect nucleotides areinserted into the newly synthesized DNA strand and escape theproofreading function of DNA polymerases. Indel loops commonly arise inthe context of microsatellites—highly polymorphic short repetitive DNAsequences distributed throughout both prokaryotic and eukaryoticgenomes. Typically, at microsatellites, the template and primer strandsare prone to slippage (dissociation and reannealing) during replication,which can generate loop structures and a discordant number of repeatunits between the template and newly synthesized strand.

DNA mismatch repair is a bidirectional excision and re-synthesis systemthat initiates at a defined strand scission 3′- or 5′- to a mismatch;the excision tract extends just past the mismatch. MMR can be dividedinto four steps: 1) mismatch recognition by MSH proteins; 2) recruitmentof MLH proteins that connect the mismatch recognition signal to wherethe distant DNA strand scission begins; 3) excision of the errant DNAstrand, and 4) re-synthesis of the excision gap using the remaining DNAstrand as a template [1]. MMR is a highly conserved biological pathway.In humans, mismatch recognition by hMutSα (MSH2-MSH6) or hMutSβ(MSH2-MSH3) initiates the MMR pathway. Binding of hMutSα or hMutSβ tothe mismatch site results in the recruitment of MutLα (MLH1-PMS2) toform a ternary complex whose protein-protein and protein-DNAinteractions are modulated by ATP/ADP cofactors. Proliferating cellnuclear antigen (PCNA) may play a role in the recruitment of MMRproteins to the vicinity of the replication fork [1]. PCNA may alsoactivate a latent endonuclease activity in eukaryotic MutLα proteins.After DNA incision, exonuclease 1 (EXO1) is recruited which excises thenewly synthesized DNA strand and the DNA excision gap is re-synthesizedby DNA polymerase 6 (Pol6). When DNA re-synthesis is complete, theremaining nick is ligated by DNA ligase to restore the integrity of theduplex [2]. Consistent with this function, MMR is an important tumorsuppressor pathway that is lost in up to 40% of sporadic cancers.Moreover, individuals with germline mutations in MMR genes developcancer predisposition conditions.

Lynch Syndrome (LS, formerly designated as hereditary non-polyposiscolorectal cancer) is the most common cause of hereditary colorectalcancer (CRC), accounting for 2-5% of all cases. LS is also characterizedby an increased risk of malignancies at certain extracolonic sites suchas the endometrium, ovary, stomach and small bowel, among others [3]. LShas an autosomal dominant inheritance pattern and is caused by germlinemutations in MMR genes MLH1, MSH2, MSH6 or PMS2. Gene expression fromthe one wild-type allele is sufficient for adequate MMR activity until asecond hit inactivates the wild-type allele leading to MMR deficiency.

Constitutional mismatch repair deficiency (CMMRD) syndrome is a distinctchildhood cancer predisposition syndrome that results from biallelicgermline mutations in one of the four MMR genes, MLH1, MSH2, MSH6 orPMS2. Patients may have either homozygous biallelic alterations orheterozygous alterations of MMR genes.

MMR-deficient cancers are commonly and typically characterized by theaccumulation of DNA mutations at higher rates than normal cells andother tumours; for example, CMMRD tumours commonly have anultra-hypermutated phenotype (>250 substitution mutations/Mb) [4]. MMRdeficiency also results in gains or losses in the repeat length ofmicrosatellites, referred to as microsatellite instability (MSI).Cancers that possess more than 40% microsatellite variations (positivefor two or more of five microsatellite markers routinely tested) aredescribed as high frequency MSI (MSI-H). Tumours that have no MSI aremicrosatellite stable (MSS) and those that possess less than 40%microsatellite variations (one out of the five markers showingmicrosatellite instability) are low frequency MSI (MSI-L) [5]. MSIanalysis is a widely used diagnostic biomarker of MMR-deficient tumoursand MSI status is linked with a high prevalence of frameshift (FS)mutations that can occur because of insertion/deletion within codingmicrosatellites. In addition to altering downstream functions of theprotein, the FS creates a new amino acid sequence that serves as asubstrate for antigen processing and presentation [6], stimulating theactivation of CD8+ T cells (class I) and the “helper” function of CD4+ Tcells (class II).

Cancers with a greater number of neoantigens are more prone to immunesurveillance and have an increased likelihood of responding toimmunotherapy [7]; higher neoantigen load is associated with overalllymphocytic infiltration, TILs, memory T cells, and survival incolorectal cancer [8, 9]. This feature supports a rationale forimmunotherapy-based treatment strategies [6]. Consistent with thisnotion, immune checkpoint inhibitors now offer a significant therapeuticadvance in the treatment of MMR-deficient cancers. Inhibitors of PD-1;for example, pembrolizumab (Keytruda) and nivolumab (Opdivo), have beenapproved by the Food and Drug Administration (FDA) for patients withMMR-D or MSI-H metastatic CRC based upon the significant survivalbenefit they provide. The CTLA-4 inhibitor ipilimumab (Yervoy), has beenapproved for use in combination with nivolumab for the treatment ofMMR-D or MSI-H CRC patients who were previously treated withchemotherapy. Importantly, the FDA has approved the use of pembrolizumabin MMR-D/MSI-H cancers regardless of histological tumour type [10].

It is now accepted that clinical responses to immune checkpointinhibitors require the existence of tumour neoantigens and infiltrationof T cells that recognize such neoantigens. Higher neoantigen load isassociated with response to CTLA-4 and PD-1 blockade in patients withmelanoma and non-small-cell lung cancer [11, 12, 13]. The number ofneoantigens is linked to TMB, and several large studies have confirmedthat high TMB correlates with enhanced checkpoint inhibitor responsesand improved overall survival in certain tumour types, such asurothelial carcinoma [14], non-small cell lung cancer [15-18] and smallcell lung cancer [19].

Germano et al. recently proposed that MMR inactivation through silencingof MLH1 increases TMB and leads to “dynamic mutational profiles”,resulting in persistent renewal of neoantigens both in vitro and invivo. This triggers immune surveillance and leads to the control oftumour growth, particularly in combination with immune checkpointinhibition, in mouse models [20]. Similar results are observed uponsilencing of MSH2 [21].

Guan et al. and Lu et al. report that MLH1 deficiency leads to cytosolicDNA release, activation of the cGAS-STING pathway and IFN-3 production.Guan et al. demonstrate that MLH1 loss leads to DNA hyperexcision, RPAexhaustion, chromosomal instability and accumulation of cytosolic DNA.Lu et al. report that the sensing of cytosolic DNA by the cGAS STINGpathway contributes to the clinical benefit of immunotherapy in patientsharboring MMR deficient tumours. Together these reports suggest thatabrogation of MMR activity may elicit beneficial immune activationthrough activation of the cGAS-STING pathway.

There is therefore a robust biological and clinical rationalehighlighting the need for inhibitors that target the MLH1 and/or PMS2proteins, key components of DNA MMR to reawaken an anti-tumour immuneresponse.

Thus, the present invention provides methods for the treatment of cancerby binding to and modulating the function of the DNA MMR components MLH1and/or PMS2 using small molecules as single agents and in combinationwith immunotherapy agents, other DNA damage response pathway modulatorsand/or standard-of-care chemotherapeutic agents.

Outside of the cancer field, triplet repeat disorders comprise over 30human neurodegenerative and neuromuscular inherited diseases such asHuntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile Xsyndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellarataxias (SCAs). Such disorders are characterized by the expansion ofsimple repeats in genomic DNA. These unstable repeats are commonly foundat different regions of several genes and their expansion can causedisease by a variety of both loss- and gain-of-function pathways, forinstance through interfering with the expression or properties of thegene products, or by affecting splicing or antisense regulation. Severalmechanisms including errors during DNA replication, meioticrecombination, transcription, DNA repair, and chromatin remodeling havebeen proposed to contribute to repeat instability, which can occur atvarious stages of the cell cycle. There is evidence that a functionalMMR pathway is required for maintaining the stability of microsatellitesequences: for example, Msh2−/− transgenic mice bearing a copy of thehuman HD exon 1 (containing the CAG repeats) showed reduced expansion ofthe introduced (CAG)n repeats when compared with Msh2+/+HD exon 1 micecounterparts [22].

Thus, there is a further need for compounds that target MLH1 and/or PMS2components of the DNA MMR process for treating triplet repeat disorders.The present invention was devised with the foregoing in mind.

REFERENCES

-   1. Martin-Lopez, J. V. and R. Fishel, The mechanism of mismatch    repair and the functional analysis of mismatch repair defects in    Lynch syndrome. Fam Cancer, 2013. 12(2): p. 159-68.-   2. Liu, D., G. Keijzers, and L. J. Rasmussen, DNA mismatch repair    and its many roles in eukaryotic cells. Mutat Res, 2017. 773: p.    174-187.-   3. Lynch, H. T., et al., Review of the Lynch syndrome: history,    molecular genetics, screening, differential diagnosis, and    medicolegal ramifications. Clin Genet, 2009. 76(1): p. 1-18.-   4. Shlien, A., et al., Combined hereditary and somatic mutations of    replication error repair genes result in rapid onset of    ultra-hypermutated cancers. Nat Genet, 2015. 47(3): p. 257-62-   5. Sehgal, R., et al., Lynch syndrome: an updated review. Genes    (Basel), 2014. 5(3): p. 497-507-   6. Willis, J. A., et al., Immune Activation in Mismatch    Repair-Deficient Carcinogenesis: More Than Just Mutational Rate.    Clin Cancer Res, 2019.-   7. Gubin, M. M. and R. D. Schreiber, CANCER. The odds of    immunotherapy success. Science, 2015. 350(6257): p. 158-9.-   8. Kloor, M. and M. von Knebel Doeberitz, The Immune Biology of    Microsatellite-Unstable Cancer. Trends Cancer, 2016. 2(3): p.    121-133.-   9. Giannakis, M., et al., Genomic Correlates of Immune-Cell    Infiltrates in Colorectal Carcinoma. Cell Rep, 2016. 17(4): p. 1206.-   10. Lemery, S., P. Keegan, and R. Pazdur, First FDA Approval    Agnostic of Cancer Site—When a Biomarker Defines the Indication. N    Engl J Med, 2017. 377(15): p. 1409-1412.-   11. Le, D. T., et al., PD-1 Blockade in Tumors with Mismatch-Repair    Deficiency. N Engl J Med, 2015. 372(26): p. 2509-20.-   12. Rizvi, N. A., et al., Cancer immunology. Mutational landscape    determines sensitivity to PD-1 blockade in non-small cell lung    cancer. Science, 2015. 348(6230): p. 124-8.-   13. Van Allen, E. M., et al., Genomic correlates of response to    CTLA-4 blockade in metastatic melanoma. Science, 2015. 350(6257): p.    207-211.-   14. Rosenberg, J E., et al., Atezolizumab in patients with locally    advanced and metastatic urothelial carcinoma who have progressed    following treatment with platinum-based chemotherapy: a single-arm,    multicentre, phase 2 trial. Lancet, 2016. 387(10031): p. 1909-20.-   15. Hellmann, M. D., et al., Genomic Features of Response to    Combination Immunotherapy in Patients with Advanced Non-Small-Cell    Lung Cancer. Cancer Cell, 2018. 33(5): p. 843-852 e4.-   16. Rizvi, H., et al., Molecular Determinants of Response to    Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1    (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer    Profiled With Targeted Next-Generation Sequencing. J Clin    Oncol, 2018. 36(7): p. 633-641.-   17. Carbone, D. P., et al., First-Line Nivolumab in Stage IV or    Recurrent Non-Small-Cell Lung Cancer. N Engl J Med, 2017.    376(25): p. 2415-2426.-   18. Hellmann, M. D., et al., Nivolumab plus Ipilimumab in Lung    Cancer with a High Tumor Mutational Burden. N Engl J Med, 2018.    378(22): p. 2093-2104.-   19. Hellmann, M. D., et al., Tumor Mutational Burden and Efficacy of    Nivolumab Monotherapy and in Combination with Ipilimumab in    Small-Cell Lung Cancer. Cancer Cell, 2018. 33(5): p. 853-861 e4.-   20. Germano, G., et al., Inactivation of DNA repair triggers    neoantigen generation and impairs tumour growth. Nature, 2017.    552(7683): p. 116-120.-   21. Mandal, R., et al., Genetic diversity of tumors with mismatch    repair deficiency influences anti-PD-1 immunotherapy response.    Science, 2019. 364(6439): p. 485-491.-   22. Lu, C., et al. DNA sensing in mismatch repair-deficient tumor    cells is essential for anti-tumor immunity. Cancer Cell. 2021, 39    (1), 96-108.-   23. Guan J., et al., MLH1 deficiency-triggered DNA hyperexcision by    exonuclease 1 activates the cGAS-STING pathway. Cancer Cell. 2021,    39 (1), 109-121,-   24. Manley, K., et al., Msh2 deficiency prevents in vivo somatic    instability of the CAG repeat in Huntington disease transgenic mice.    Nat Genet, 1999. 23(4): p. 471-3.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention there is provided acompound, or a pharmaceutically acceptable salt, hydrate or solvatethereof, as defined herein.

According to a further aspect of the present invention, there isprovided a pharmaceutical composition comprising a compound as definedherein, or a pharmaceutically acceptable salt, hydrate or solvatethereof, in admixture with a pharmaceutically acceptable diluent orcarrier.

According to a further aspect of the present invention, there isprovided a method of inhibiting MLH1 and/or PMS2 activity (e.g. MLH1activity or PMS2 activity or MLH1 and PMS2 activity), in vitro or invivo, said method comprising contacting a cell with an effective amountof a compound or a pharmaceutically acceptable salt, hydrate or solvatethereof as defined herein.

According to a further aspect of the present invention, there isprovided a method of treating a disease or disorder in which MLH1 and/orPMS2 activity (e.g. MLH1 activity or PMS2 activity or MLH1 and PMS2activity) is implicated in a patient in need of such treatment, saidmethod comprising administering to said patient a therapeuticallyeffective amount of a compound or a pharmaceutically acceptable salt,hydrate or solvate thereof as defined herein, or a pharmaceuticalcomposition as defined herein.

According to a further aspect of the present invention, there isprovided a method of treating a proliferative disorder in a patient inneed of such treatment, said method comprising administering to saidpatient a therapeutically effective amount of a compound or apharmaceutically acceptable salt, hydrate or solvate thereof as definedherein, or a pharmaceutical composition as defined herein.

According to a further aspect of the present invention, there isprovided a method of treating cancer in a patient in need of suchtreatment, said method comprising administering to said patient atherapeutically effective amount of a compound or a pharmaceuticallyacceptable salt, hydrate or solvate thereof as defined herein, or apharmaceutical composition as defined herein.

According to a further aspect of the present invention, there isprovided a method of treating a triplet disorder (e.g. Huntington'sdisease (HD), myotonic dystrophy type 1 (DM1), fragile X syndrome type A(FRAXA), Friedreich's ataxia (FRDA), and spinocerebellar ataxias (SCAs))in a patient in need of such treatment, said method comprisingadministering to said patient a therapeutically effective amount of acompound or a pharmaceutically acceptable salt, hydrate or solvatethereof as defined herein, or a pharmaceutical composition as definedherein.

According to a further aspect of the present invention, there isprovided a compound, or a pharmaceutically acceptable salt, hydrate orsolvate thereof, or a pharmaceutical composition as defined herein foruse in therapy.

According to a further aspect of the present invention, there isprovided a compound, or a pharmaceutically acceptable salt, hydrate orsolvate thereof, or a pharmaceutical composition as defined herein foruse as a medicament.

According to a further aspect of the present invention, there isprovided a compound or a pharmaceutically acceptable salt, hydrate orsolvate thereof as defined herein, or a pharmaceutical composition asdefined herein, for use in the treatment of a proliferative disorder.

According to a further aspect of the present invention, there isprovided a compound, or a pharmaceutically acceptable salt, hydrate orsolvate thereof, or a pharmaceutical composition as defined herein foruse in the treatment of cancer. In a particular embodiment, the canceris human cancer.

According to a further aspect of the present invention, there isprovided a compound, or a pharmaceutically acceptable salt, hydrate orsolvate thereof, or a pharmaceutical composition as defined herein foruse in the treatment of a triplet disorder. In a particular embodiment,the triplet disorder is selected from the group consisting ofHuntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile Xsyndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellarataxias (SCAs).

According to a further aspect of the present invention, there isprovided a compound, or a pharmaceutically acceptable salt, hydrate orsolvate thereof, as defined herein for use in the inhibition of MLH1and/or PMS2 activity (e.g. MLH1 activity or PMS2 activity or MLH1 andPMS2 activity).

According to a further aspect of the present invention, there isprovided a compound, or a pharmaceutically acceptable salt, hydrate orsolvate thereof, as defined herein for use in the treatment of a diseaseor disorder in which MLH1 and/or PMS2 activity (e.g. MLH1 activity orPMS2 activity or MLH1 and PMS2 activity) is implicated.

According to a further aspect of the present invention, there isprovided the use of a compound, or a pharmaceutically acceptable salt,hydrate or solvate thereof, as defined herein in the manufacture of amedicament for the treatment of a proliferative disorder.

According to a further aspect of the present invention, there isprovided the use of a compound, or a pharmaceutically acceptable salt,hydrate or solvate thereof, as defined herein in the manufacture of amedicament for the treatment of cancer.

According to a further aspect of the present invention, there isprovided the use of a compound, or a pharmaceutically acceptable salt,hydrate or solvate thereof, as defined herein in the manufacture of amedicament for the treatment of a triplet disorder. In a particularembodiment, the triplet disorder is selected from the group consistingof Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile Xsyndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellarataxias (SCAs).

According to a further aspect of the present invention, there isprovided a use of a compound, or a pharmaceutically acceptable salt,hydrate or solvate thereof, as defined herein in the manufacture of amedicament for the inhibition of MLH1 and/or PMS2 activity (e.g. MLH1activity or PMS2 activity or MLH1 and PMS2 activity).

According to a further aspect of the present invention, there isprovided a use of a compound, or a pharmaceutically acceptable salt,hydrate or solvate thereof, as defined herein in the manufacture of amedicament for the treatment of a disease or disorder in which MLH1and/or PMS2 activity (e.g. MLH1 activity or PMS2 activity or MLH1 andPMS2 activity) is implicated.

According to a further aspect of the present invention, there isprovided a process for preparing a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, as defined herein.

According to a further aspect of the present invention, there isprovided a compound, or a pharmaceutically acceptable salt, hydrate orsolvate thereof, obtainable by, or obtained by, or directly obtained bya process of preparing a compound as defined herein.

According to a further aspect of the present invention, there areprovided novel intermediates as defined herein which are suitable foruse in any one of the synthetic methods set out herein.

In the above-outlined aspects of the invention, the proliferativedisorder is suitably cancer, and the cancer is suitably a human cancer.In particular, the compounds of the present invention will be useful forthe treatment of any cancer in which mis-match repair inhibition and/orcGAS/STING pathway activation is beneficial. Any suitable cancer may betargeted (e.g. adenoid cystic carcinoma, adrenal gland tumor,amyloidosis, anal cancer, appendix cancer, astrocytoma,ataxia-telangiectasia, Beckwith-Wiedemann Syndrome, bile duct cancer(cholangiocarcinoma), Birt-Hogg-Dubé Syndrome, bladder cancer, bonecancer, brain stem glioma, brain tumor, breast cancer, Carney Complex,central nervous system tumors, cervical cancer, colorectal cancer,Cowden Syndrome, craniopharyngioma, desmoplastic infantileganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer,eyelid cancer, familial adenomatous polyposis, familial GIST, familialmalignant melanoma, familial non-VHL clear cell renal cell carcinoma,familial pancreatic cancer, gallbladder cancer, gastrointestinal stromaltumor—GIST, germ cell tumor, gestational trophoblastic disease, head andneck cancer, hereditary breast and ovarian cancer, hereditary diffusegastric cancer, hereditary leiomyomatosis and renal cell cancer,hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditarypapillary renal carcinoma, juvenile polyposis syndrome, kidney cancer,lacrimal gland tumor, laryngeal and hypopharyngeal cancer, leukemia(acute lymphoblastic leukamia (ALL), acute myeloid leukemia (AML),B-cell prolymphocytic leukemia, hairy cell leukemia, chronic lymphocyticleukemia (CLL), chronic myeloid leukemia (CML), chronic T-celllymphocytic leukemia, eosinophilic leukemia), Li-Fraumeni Syndrome,liver cancer, lung cancer (non-small cell lung cancer, small cell lungcancer), Lymphoma (Hodgkin, non-Hodgkin), Lynch Syndrome, mastocytosis,medulloblastoma, melanoma, meningioma, mesothelioma, multiple endocrineneoplasia Type 1 & 2, multiple myeloma, MUTYH (or MYH)-associatedpolyposis, myelodysplastic syndromes (MDS), nasal cavity and paranasalsinus Cancer, nasopharyngeal Cancer, neuroblastoma, neuroendocrinetumors (e.g. of the gastrointestinal tract, lung or pancreas),neurofibromatosis Type 1 & 2, nevoid basal cell carcinoma syndrome, oraland oropharyngeal cancer, osteosarcoma, ovarian/fallopiantube/peritoneal cancer, pancreatic cancer, parathyroid cancer, penilecancer, Peutz-Jeghers Syndrome, pheochromocytoma, paraganglioma,pituitary gland tumor, pleuropulmonary blastoma, prostate cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g.Kaposi or soft tissue), skin cancer, small bowel cancer, stomach cancer,testicular cancer, thymoma and thymic carcinoma, thyroid cancer,tuberous sclerosis complex, uterine cancer, vaginal cancer, VonHippel-Lindau syndrome, vulvar cancer, Waldenstrom's macroglobulinemia,Werner syndrome, Wilms Tumor and xeroderma pigmentosum). Particularcancers of interest include haematological cancers such as lymphomas(including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma(FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma(AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL) andchronic myeloid leukaemia (CML)), multiple myeloma, breast cancer,non-small cell lung cancer (NSCLC), colorectal cancer, endometrialcancer, gastro-oesophageal cancer, neuroendocrine cancers,osteosarcomas, prostate cancer, pancreatic cancer, small intestinecancer, bladder cancer, rectal cancer, cholangiocarcinoma, CNS cancer,thyroid cancer, head and neck cancer, oesophageal cancer, and ovariancancer.

Features, including optional, suitable, and preferred features inrelation to one aspect of the invention may also be features, includingoptional, suitable and preferred features in relation to any otheraspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the following meanings set out below.

It is to be appreciated that references to “treating” or “treatment”include prophylaxis as well as the alleviation of established symptomsof a condition. “Treating” or “treatment” of a state, disorder orcondition therefore includes: (1) preventing or delaying the appearanceof clinical symptoms of the state, disorder or condition developing in ahuman that may be afflicted with or predisposed to the state, disorderor condition but does not yet experience or display clinical orsubclinical symptoms of the state, disorder or condition, (2) inhibitingthe state, disorder or condition, i.e., arresting, reducing or delayingthe development of the disease or a relapse thereof (in case ofmaintenance treatment) or at least one clinical or subclinical symptomthereof, or (3) relieving or attenuating the disease, i.e., causingregression of the state, disorder or condition or at least one of itsclinical or subclinical symptoms.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated. It should be understood that in, for example, a human orother mammal, a therapeutically effective amount can be determinedexperimentally in a laboratory or clinical setting, or a therapeuticallyeffective amount may be the amount required by the guidelines of theUnited States Food and Drug Administration (FDA) or equivalent foreignregulatory body, for the particular disease and subject being treated.It should be appreciated that determination of proper dosage forms,dosage amounts, and routes of administration is within the level ofordinary skill in the pharmaceutical and medical arts.

As used herein by themselves or in conjunction with another term orterms, “subject(s)” and “patient(s)”, refer to animals (e.g. mammals),particularly humans. Suitably, the “subject(s)” and “patient(s)” may bea non-human animal (e.g. livestock and domestic pets) or a human.

As used herein by itself or in conjunction with another term or terms,“pharmaceutically acceptable” refers to materials that are generallychemically and/or physically compatible with other ingredients (such as,for example, with reference to a formulation), and/or is generallyphysiologically compatible with the recipient (such as, for example, asubject) thereof.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups. References to individual alkyl groups suchas “propyl” are specific for the straight chain version only andreferences to individual branched chain alkyl groups such as “isopropyl”are specific for the branched chain version only. For example,“(1-6C)alkyl” includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl andt-butyl.

The term “(m-nC)” or “(m-nC) group” used alone or as a prefix, refers toany group having m to n carbon atoms.

An “alkylene” group is an alkyl group that is positioned between andserves to connect two other chemical groups. Thus, “(1-6C)alkylene”means a linear saturated divalent hydrocarbon radical of one to sixcarbon atoms or a branched saturated divalent hydrocarbon radical ofthree to six carbon atoms, for example, methylene (—CH₂—), the ethyleneisomers (—CH(CH₃)— and —CH₂CH₂—), the propylene isomers (—CH(CH₃)CH₂—,—CH(CH₂CH₃)—, —C(CH₃)₂—, and —CH₂CH₂CH₂—), pentylene(—CH₂CH₂CH₂CH₂CH₂—), and the like.

The term “alkyenyl” refers to straight and branched chain alkyl groupscomprising 2 or more carbon atoms, wherein at least one carbon-carbondouble bond is present within the group. Examples of alkenyl groupsinclude ethenyl, propenyl and but-2,3-enyl and includes all possiblegeometric (E/Z) isomers.

The term “alkynyl” refers to straight and branched chain alkyl groupscomprising 2 or more carbon atoms, wherein at least one carbon-carbontriple bond is present within the group. Examples of alkynyl groupsinclude acetylenyl and propynyl.

“(m-nC)cycloalkyl” means a saturated hydrocarbon ring system containingfrom m to n number of carbon atoms. Exemplary cycloalkyl groups include,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and bicyclo[2.2.1]heptyl.

The term “alkoxy” refers to O-linked straight and branched chain alkylgroups. Examples of alkoxy groups include methoxy, ethoxy and t-butoxy.

The term “haloalkyl” is used herein to refer to an alkyl group in whichone or more hydrogen atoms have been replaced by halogen (e.g. fluorine)atoms. Examples of haloalkyl groups include —CH₂F, —CHF₂ and —CF₃.

The term “halo” or “halogeno” refers to fluoro, chloro, bromo and iodo,suitably fluoro, chloro and bromo, more suitably, fluoro and chloro.

The term “carbocyclyl”, “carbocyclic” or “carbocycle” means anon-aromatic saturated or partially saturated monocyclic, fused,bridged, or spiro bicyclic carbon-containing ring system(s). Monocycliccarbocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ringatoms. Bicyclic carbocycles contain from 6 to 17 member atoms, suitably7 to 12 member atoms, in the ring. Bicyclic carbocyclic(s) rings may befused, spiro, or bridged ring systems. Examples of carbocyclic groupsinclude cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl andspiro[3.3]heptanyl.

The term “heterocyclyl”, “heterocyclic” or “heterocycle” means anon-aromatic saturated or partially saturated monocyclic, fused,bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclicheterocyclic rings contain from about 3 to 12 (suitably from 3 to 7)ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selectedfrom nitrogen, oxygen or sulfur in the ring. Bicyclic heterocyclescontain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in thering. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridgedring systems. Examples of heterocyclic groups include cyclic ethers suchas oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substitutedcyclic ethers. Heterocycles containing nitrogen include, for example,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl,tetrahydropyrazolyl, and the like. Typical sulfur containingheterocycles include tetrahydrothienyl, dihydro-1,3-dithiol,tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocyclesinclude dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl,tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl,tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl,tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl,octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocyclescontaining sulfur, the oxidized sulfur heterocycles containing SO or SO₂groups are also included. Examples include the sulfoxide and sulfoneforms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene1,1-dioxide and thiomorpholinyl 1,1-dioxide. Heterocycles may comprise 1or 2 oxo (═O) or thioxo (═S) substituents. A suitable value for aheterocyclyl group which bears 1 or 2 oxo (═O) or thioxo (═S)substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl,2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.Particular heterocyclyl groups are saturated monocyclic 3 to 7 memberedheterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen,oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl,tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl orhomopiperazinyl. As the skilled person would appreciate, any heterocyclemay be linked to another group via any suitable atom, such as via acarbon or nitrogen atom. However, reference herein to piperidino ormorpholino refers to a piperidin-1-yl or morpholin-4-yl ring that islinked via the ring nitrogen.

By “bridged ring systems” is meant ring systems in which two rings sharemore than two atoms, see for example Advanced Organic Chemistry, byJerry March, 4^(th) Edition, Wiley Interscience, pages 131-133, 1992.Examples of bridged heterocyclyl ring systems include,aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane,aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.

By “spiro bi-cyclic ring systems” we mean that the two ring systemsshare one common spiro carbon atom, i.e. the heterocyclic ring is linkedto a further carbocyclic or heterocyclic ring through a single commonspiro carbon atom. Examples of spiro ring systems include6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane,2-azaspiro[3.3]heptanes, 2-oxa-6-azaspiro[3.3]heptanes,7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane,2-oxa-7-azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

As used herein by itself or in conjunction with another term or terms,“aromatic” refers to monocyclic and polycyclic ring systems containing4n+2 pi electrons, where n is an integer. Aromatic should be understoodas referring to and including ring systems that contain only carbonatoms (i.e. “aryl”) as well as ring systems that contain at least oneheteroatom selected from N, O or S (i.e. “heteroaromatic” or“heteroaryl”). An aromatic ring system can be substituted orunsubstituted.

As used herein by itself or in conjunction with another term or terms,“non-aromatic” refers to a monocyclic or polycyclic ring system havingat least one double bond that is not part of an extended conjugated pisystem. As used herein, non-aromatic refers to and includes ring systemsthat contain only carbon atoms as well as ring systems that contain atleast one heteroatom selected from N, O or S. A non-aromatic ring systemcan be substituted or unsubstituted.

The term “heteroaryl” or “heteroaromatic” means an aromatic mono-, bi-,or polycyclic ring incorporating one or more (for example 1-4,particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen orsulfur. The term heteroaryl includes both monovalent species anddivalent species. Examples of heteroaryl groups are monocyclic andbicyclic groups containing from five to twelve ring members, and moreusually from five to ten ring members. The heteroaryl group can be, forexample, a 5- or 6-membered monocyclic ring or a 9- or 10-memberedbicyclic ring, for example a bicyclic structure formed from fused fiveand six membered rings or two fused six membered rings. Each ring maycontain up to about four heteroatoms typically selected from nitrogen,sulfur and oxygen. Typically the heteroaryl ring will contain up to 3heteroatoms, more usually up to 2, for example a single heteroatom. Inone embodiment, the heteroaryl ring contains at least one ring nitrogenatom. The nitrogen atoms in the heteroaryl rings can be basic, as in thecase of an imidazole or pyridine, or essentially non-basic as in thecase of an indole or pyrrole nitrogen. In general the number of basicnitrogen atoms present in the heteroaryl group, including any aminogroup substituents of the ring, will be less than five.

Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl,isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl,naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl,pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl,5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl,4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl,imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. “Heteroaryl”also covers partially aromatic bi- or polycyclic ring systems wherein atleast one ring is an aromatic ring and one or more of the other ring(s)is a non-aromatic, saturated or partially saturated ring, provided atleast one ring contains one or more heteroatoms selected from nitrogen,oxygen or sulfur. Examples of partially aromatic heteroaryl groupsinclude for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl,2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl,dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl,2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl,indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl,1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

Examples of five membered heteroaryl groups include but are not limitedto pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl,oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, triazolyl and tetrazolyl groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

A bicyclic heteroaryl group may be, for example, a group selected from:a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ringcontaining 1, 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5-or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ringfused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ringheteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-memberedring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5-or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ringfused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; athiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ringheteroatoms; an isothiazole ring fused to a 5- or 6-membered ringcontaining 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or6-membered ring containing 1, 2 or 3 ring heteroatoms; a furan ringfused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ringcontaining 1, 2 or 3 ring heteroatoms; and a cyclopentyl ring fused to a5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ringheteroatoms.

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl,indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl(e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl andpyrazolopyridinyl groups.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinolinyl,isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl,chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl,benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, naphthyridinyl and pteridinyl groups.

The term “aryl” means a cyclic or polycyclic aromatic ring having from 5to 12 carbon atoms. The term aryl includes both monovalent species anddivalent species. Examples of aryl groups include, but are not limitedto, phenyl, biphenyl, naphthyl and the like. In a particular embodiment,an aryl is phenyl.

This specification also makes use of several composite terms to describegroups comprising more than one functionality. Such terms will beunderstood by a person skilled in the art. For example(3-6C)cycloalkyl(m-nC)alkyl comprises (m-nC)alkyl substituted by(3-6C)cycloalkyl.

The term “optionally substituted” refers to either groups, structures,or molecules that are substituted and those that are not substituted.The term “wherein a/any CH, CH₂, CH₃ group or heteroatom (i.e. NH)within a R¹ group is optionally substituted” suitably means that (any)one of the hydrogen radicals of the R¹ group is substituted by arelevant stipulated group.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups. In some embodiments, one ormore refers to one, two or three. In another embodiment, one or morerefers to one or two. In a particular embodiment, one or more refers toone.

The phrase “compound of the invention” means those compounds which aredisclosed herein, both generically and specifically.

“About” when used herein in conjunction with a measurable value such as,for example, an amount or a period of time and the like, is meant toencompass reasonable variations of the value, for instance, to allow forexperimental error in the measurement of said value.

Compounds

In one aspect, the present invention relates to compounds, orpharmaceutically acceptable salts, hydrates or solvates thereof, havingthe structural Formula (I), shown below:

wherein

R¹ and R³ are independently selected from the group consisting ofhydrogen, hydroxy, halogen and (1-4C)alkoxy, with the proviso that atleast one of R¹ and R³ is hydroxy;

R² is hydrogen or fluoro;

R⁴ is selected from the group consisting of hydrogen, halogen,(1-6C)alkyl, (3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl, whereinthe said (1-6C)alkyl is optionally substituted by one or more R^(5a) andthe said (3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl groups areoptionally substituted with one or more R^(5b); where each R^(5a) isindependently selected from halogen or (1-4C)alkoxy and each R^(5b) isindependently selected from the group consisting of halogen, (1-4C)alkyland (1-4C)alkoxy;

R⁶ is (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl or a 4-to 7-membered heterocyclyl ring comprising one heteroatom selected fromN, O or S, or a group having a structure according to formula (A) shownbelow:

wherein

-   -   R⁷ is hydrogen or (1-3C)alkyl;    -   n is 1 or 2;    -   R⁸ is aryl or heteroaryl, wherein the said aryl or heteroaryl is        optionally substituted with one or more R⁹; where each R⁹ is        independently selected from the group consisting of hydroxy,        cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (2-3C)alkenyl, or        (2-3C)alkynyl;

R¹⁰ is —NR¹¹R¹², wherein R¹¹ and R¹² are linked, such that, togetherwith the nitrogen atom to which they are attached, they form a 5-7membered monocyclic heterocyclic ring that is fused to either a 5-6membered monocyclic heteroaromatic ring or a benzene ring, therebyforming a 8-11 membered bicyclic heteroaryl ring;

wherein any one or more of the rings present in R¹⁰ is independentlyoptionally substituted with one or more R¹³;

each R¹³ is independently selected from the group consisting of halogen,cyano, oxo, epoxy and a group

-L¹-X¹-Q¹

wherein:

-   -   L¹ is absent or (1-3C)alkylene;    -   X¹ is absent or is selected from the group consisting of —O—,        —C(O)—, —C(O)—O—, —O—C(O)—, —S(O)₀₋₂—, —C(O)—N(R¹⁴)—,        —N(R¹⁴)—C(O)—, —NR¹⁴—, —N(R¹⁴)—C(O)—NR¹⁴—, —SO₂N(R¹)—, or        —N(R¹⁴)SO₂—, where R¹⁴ is, at each occurrence, independently        selected from the group consisting of hydrogen, hydroxy, cyano,        (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl, where any        (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl in R¹⁴ is        independently optionally substituted with one or more groups        selected from the group consisting of halogen and hydroxy;    -   Q¹ is selected from the group consisting of hydrogen,        (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl,        (3-8C)cycloalkyl(1-3C)alkyl, aryl, aryl(1-3C)alkyl,        heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl and        heteroaryl(1-3C)alkyl, wherein any (1-6C)alkyl, (2-6C)alkenyl,        (2-6C)alkynyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-3C)alkyl,        aryl, aryl(1-3C)alkyl, heterocyclyl, heterocyclyl(1-3C)alkyl,        heteroaryl or heteroaryl(1-3C)alkyl in Q¹ is optionally        substituted with one or more groups R¹⁵; and

each R¹⁵ is independently selected from the group consisting of hydroxy,cyano, oxo, halogen, (1-3C)alkyl, (1-3C)alkoxy, —NR^(15a)R^(15b),—C(O)—R^(15a), —C(O)—OR^(15a), —O—C(O)—R^(15a), —C(O)—NR^(15a)R^(15b),—N(R^(15b))C(O)—R^(15a), —S(O)₀₋₂R^(15a), —S(O)₂NR^(15a)R^(15b), and—N(R^(15b))—S(O)₂R^(15a), wherein R^(15a) and R^(15b) are eachindependently hydrogen or (1-3C)alkyl, and wherein any (1-3C)alkylmoiety present in a R^(15a) or R^(15b) group is optionally furthersubstituted by one or more substituents independently selected fromhydroxy, cyano, halogen, —OR^(15c), —NR^(15c)R^(15d) and —C(O)—R^(15c),wherein R^(15c) and R^(15d) are both independently selected fromhydrogen and (1-2C)alkyl.

In another aspect, the present invention relates to compounds, orpharmaceutically acceptable salts, hydrates or solvates thereof, havingthe structural Formula (I), shown below:

wherein

R¹ and R³ are independently selected from the group consisting ofhydrogen, hydroxy, halogen and (1-4C)alkoxy, with the proviso that atleast one of R¹ and R³ is hydroxy;

R² is hydrogen or fluoro;

R⁴ is selected from the group consisting of hydrogen, halogen,(1-6C)alkyl, (3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl, whereinthe said (1-6C)alkyl is optionally substituted by one or more R^(5a) andthe said (3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl groups areoptionally substituted with one or more R^(5b); where each R^(5a) isindependently selected from halogen or (1-4C)alkoxy and each R^(5b) isindependently selected from the group consisting of halogen, (1-4C)alkyland (1-4C)alkoxy;

R⁶ is (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl or a 4- to7-membered heterocyclyl ring comprising one heteroatom selected from N,O or S, or a group having a structure according to formula (A) shownbelow:

wherein

-   -   R⁷ is hydrogen or (1-3C)alkyl;    -   n is 1 or 2;    -   R⁸ is aryl or heteroaryl, wherein the said aryl or heteroaryl is        optionally substituted with one or more R⁹; where each R⁹ is        independently selected from the group consisting of hydroxy,        cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (2-3C)alkenyl, or        (2-3C)alkynyl;

R¹⁰ is —NR¹¹R¹², wherein R¹¹ and R¹² are linked, such that, togetherwith the nitrogen atom to which they are attached, they form a 5-7membered monocyclic heterocyclic ring that is fused to either a 5-6membered monocyclic heteroaromatic ring or a benzene ring, therebyforming a 8-11 membered bicyclic heteroaryl ring;

wherein any one or more of the rings present in R¹⁰ is independentlyoptionally substituted with one or more R¹³;

each R¹³ is independently selected from the group consisting of halogen,cyano, oxo, epoxy and a group

-L¹-X¹-Q¹

wherein:

-   -   L¹ is absent or (1-3C)alkylene;    -   X¹ is absent or is selected from the group consisting of —O—,        —C(O)—, —C(O)—O—, —O—C(O)—, —S(O)₀₋₂—, —C(O)—N(R¹⁴)—,        —N(R¹⁴)—C(O)—, —NR¹⁴—, —N(R¹⁴)—C(O)—NR¹⁴—, —SO₂N(R¹)—, or        —N(R¹⁴)SO₂—, where R¹⁴ is, at each occurrence, independently        selected from the group consisting of hydrogen, hydroxy, cyano,        (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl, where any        (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl in R¹⁴ is        independently optionally substituted with one or more groups        selected from the group consisting of halogen and hydroxy;    -   Q¹ is selected from the group consisting of hydrogen,        (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl,        aryl, heterocyclyl and heteroaryl, wherein any (1-6C)alkyl,        (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, aryl,        heterocyclyl, or heteroaryl in Q¹ is optionally substituted with        one or more groups R¹⁵; and

each R¹⁵ is independently selected from the group consisting of hydroxy,cyano, oxo, halogen, (1-3C)alkyl, (1-3C)alkoxy, —NR^(15a)R^(15b),—C(O)—R^(15a), —C(O)—OR^(15a), —O—C(O)—R^(15a), —C(O)—NR^(15a)R^(15b),—N(R^(15b))C(O)—R^(15a), —S(O)₀₋₂R^(15a), —S(O)₂NR^(15a)R^(15b), and—N(R^(15b))—S(O)₂R^(15a), wherein R^(15a) and R^(15b) are eachindependently hydrogen or (1-3C)alkyl, and wherein any (1-3C)alkylmoiety present in a R^(15a) or R^(15b) group is optionally furthersubstituted by one or more substituents independently selected fromhydroxy, cyano, halogen, —OR^(15c), —NR^(15c)R^(15d) and —C(O)—R^(15c),wherein R^(15c) and R^(15d) are both independently selected fromhydrogen and (1-2C)alkyl.

Particular compounds of the invention include, for example, compounds ofthe Formula (I), or pharmaceutically acceptable salts, hydrates and/orsolvates thereof, wherein, unless otherwise stated, each of R¹, R², R³,R⁴, R⁶ and R¹⁰ (including R¹¹ and R¹²) and any associated substituentgroups has any of the meanings defined hereinbefore or in any ofparagraphs (1) to (135) hereinafter:

-   (1) R¹ and R³ are independently selected from the group consisting    of hydrogen, hydroxy, halo and (1-2C)alkoxy, with the proviso that    at least one of R¹ and R³ is hydroxy.-   (2) R¹ and R³ are independently selected from the group consisting    of hydrogen, hydroxy, fluoro and (1-2C)alkoxy, with the proviso that    at least one of R¹ and R³ is hydroxy.-   (3) R¹ and R³ are independently selected from the group consisting    of hydrogen, hydroxy, fluoro and methoxy, with the proviso that at    least one of R¹ and R³ is hydroxy.-   (4) R¹ and R³ are both hydroxy.-   (5) R² is fluoro.-   (6) R² is hydrogen.-   (7) R⁴ is selected from the group consisting of hydrogen, halogen,    (1-4C)alkyl, (3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl,    wherein the said (1-4C)alkyl is optionally substituted by one or    more R^(5a) and the said (3-6C)cycloalkyl and    (3-6C)cycloalkyl(1-2C)alkyl groups are optionally substituted with    one or more R^(5b).-   (8) R⁴ is selected from the group consisting of hydrogen, halogen,    (1-4C)alkyl, (3-5C)cycloalkyl and (3-5C)cycloalkyl(1-2C)alkyl,    wherein the said (1-4C)alkyl is optionally substituted by one, two    or three R^(5a) and the said (3-5C)cycloalkyl and    (3-5C)cycloalkyl(1-2C)alkyl groups are optionally substituted with    one, two or three R^(5b).-   (9) R⁴ is selected from the group consisting of hydrogen, halogen,    (1-4C)alkyl, (3-5C)cycloalkyl and (3-5C)cycloalkyl(1C)alkyl, wherein    the said (1-4C)alkyl is optionally substituted by one, two or three    R^(5a) and the said (3-5C)cycloalkyl and (3-5C)cycloalkyl(1C)alkyl    groups are optionally substituted with one, two or three R^(5b).-   (10) R⁴ is selected from the group consisting of hydrogen, halogen,    (1-4C)alkyl and (3-5C)cycloalkyl, wherein the said (1-4C)alkyl is    optionally substituted by one or two R^(5a) and the said    (3-5C)cycloalkyl group is optionally substituted with one or two    R^(5b).-   (11) R⁴ is selected from the group consisting of hydrogen, fluoro,    chloro (1-4C)alkyl, cyclopropyl and cyclobutyl, wherein the said    (1-4C)alkyl is optionally substituted by one R^(5a) and the said    cyclopropyl and cyclobutyl groups are optionally substituted with    one R^(5b).-   (12) R⁴ is selected from the group consisting of hydrogen, fluoro,    chloro, methyl, ethyl iso-propyl, cyclopropyl and cyclobutyl.-   (13) R⁴ is selected from the group consisting of hydrogen, methyl,    ethyl, iso-propyl, cyclopropyl and cyclobutyl-   (14) R⁴ is selected from the group consisting of hydrogen, methyl    and ethyl.-   (15) R⁴ is selected from the group consisting of hydrogen and    methyl.-   (16) R⁴ is hydrogen.-   (17) R⁴ is methyl.-   (18) Each R^(5a) is independently selected from halogen, hydroxy or    (1-3C)alkoxy.-   (19) Each R^(5a) is independently selected from fluoro, chloro,    hydroxy or (1-2C)alkoxy.-   (20) Each R^(5a) is independently selected from fluoro, hydroxy or    methoxy.-   (21) Each R^(5b) is independently selected from the group consisting    of halogen, hydroxy, (1-3C)alkyl and (1-3C)alkoxy.-   (22) Each R^(5b) is independently selected from the group consisting    of halogen, hydroxy, (1-2C)alkyl and (1-2C)alkoxy.-   (23) Each R^(5b) is independently selected from the group consisting    of fluoro, chloro, hydroxy, (1-2C)alkyl and (1-2C)alkoxy.-   (24) Each R^(5b) is independently selected from the group consisting    of fluoro, chloro, hydroxy, methyl and methoxy.-   (25) R⁷ is hydrogen or (1-2C)alkyl.-   (26) R⁷ is (1-3C)alkyl.-   (27) R⁷ is hydrogen or methyl.-   (28) R⁷ is hydrogen.-   (29) R⁷ is methyl.-   (30) n is 1.-   (31) n is 2.-   (32) R⁸ is phenyl or 5-6 membered heteroaryl, wherein the said    phenyl or 5-6 membered heteroaryl is optionally substituted with one    or more R⁹.-   (33) R⁸ is phenyl or 5-6 membered heteroaryl containing 1, 2 or 3    ring heteroatoms independently selected from N and O, wherein the    said phenyl or 5-6 membered heteroaryl is optionally substituted    with one, two or three R⁹.-   (34) R⁸ is phenyl or 5-6 membered heteroaryl containing 1, 2 or 3    ring N atoms, wherein the said phenyl or 5-6 membered heteroaryl is    optionally substituted with one, two or three R⁹.-   (35) R⁸ has any one of the following structures:

-   -   wherein R⁹ is as defined herein (or as in any one of        paragraphs (44) to (50) below), each m¹ is independently 0, 1, 2        or 3; and each m² is independently 0, 1 or 2.

-   (36) R⁸ has the following structure:

-   -   wherein m¹ is 0, 1, 2 or 3 and R⁹ is as defined herein (or as in        any one of paragraphs (44) to (50) below).

-   (37) R⁸ has any one of the following structures:

-   -   wherein R⁹ is as defined herein (or as in any one of        paragraphs (44) to (50) below).

-   (38) R⁸ has any one of the following structures:

-   (39) R³ has the following structure:

-   (40) Each m¹ is independently 0, 1 or 2;-   (41) Each m¹ is independently 0 or 1;-   (42) Each m¹ is 0.-   (43) Each m² is independently 0 or 1;-   (44) Each R⁹ is independently selected from the group consisting of    cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, (2-3C)alkenyl or    (2-3C)alkynyl.-   (45) Each R⁹ is independently selected from the group consisting of    halogen, (1-3C)alkyl, (1-3C)alkoxy, (2-3C)alkenyl or (2-3C)alkynyl.-   (46) Each R⁹ is independently selected from the group consisting of    halogen, (1-3C)alkyl, (1-3C)alkoxy, (2C)alkenyl or (2C)alkynyl.-   (47) Each R⁹ is independently selected from the group consisting of    halogen, (1-2C)alkyl, (1-2C)alkoxy, (2C)alkenyl and (2C)alkynyl.-   (48) Each R⁹ is independently selected from the group consisting of    fluoro, chloro, (1-3C)alkyl and (1-3C)alkoxy.-   (49) Each R⁹ is independently selected from the group consisting of    fluoro, (1-2C)alkyl and (1-2C)alkoxy.-   (50) Each R⁹ is independently selected from the group consisting of    fluoro, methyl and methoxy.-   (51) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form a 5-7 membered monocyclic    heterocyclic ring that is fused to either a 5-6 membered monocyclic    heteroaromatic ring or a benzene ring, thereby forming a 8-11    membered bicyclic heteroaryl ring; wherein any of which rings is    optionally substituted with one or more R¹³.-   (52) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form a 5-6 membered monocyclic    heterocyclic ring that is fused to either a 5-6 membered monocyclic    heteroaromatic ring or a benzene ring, thereby forming a 8-10    membered bicyclic heteroaryl ring; wherein any of which rings is    optionally substituted with up to two R¹³.-   (53) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein        -   v² and v³ are each independently 1 or 2;        -   W¹ is CH, N or O;        -   each ring A is a benzene ring or a 5-6 membered            heteroaromatic ring; and any ring is optionally substituted            with one or two R¹³.

-   (54) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein        -   v² and v³ are each independently 1 or 2;        -   W¹ is CH, N or O;    -   each ring A is a benzene ring or a 5-6 membered heteroaromatic        ring containing 1, 2 or 3 heteroatoms independently selected        from N and O;    -   each R^(13a) is independently selected from the group consisting        of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any        (1-3C)alkyl and (1-3C)alkoxy in R^(13a) is optionally        substituted with one or more groups independently selected from        the group consisting of hydroxy and halo;    -   each q² is independently 0, 1 or 2; and        -   each q³ is independently 0 or 1.

-   (55) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein        -   v¹ is 1, 2 or 3;        -   v² and v³ are each independently 1 or 2;        -   W¹ is CH, N or O;    -   each ring A is a benzene ring or a 5-6 membered heteroaromatic        ring containing 1, 2 or 3 N atoms;    -   each R^(13a) is independently selected from the group consisting        of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any        (1-3C)alkyl and (1-3C)alkoxy in R^(13a) is optionally        substituted with one or more groups independently selected from        the group consisting of hydroxy and halo;    -   each q² is independently 0, 1 or 2; and        -   each q³ is independently 0 or 1.

-   (56) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein        -   each q² is independently 0 or 1;        -   each q³ is independently 0, 1 or 2;        -   v² and v³ are each independently 1 or 2;    -   W², W³ and W⁴ are each independently CH, N or O, providing that        only zero, one or two of W², W³ and W⁴ are N or O;    -   W⁵, W⁶, W⁷ and W⁸ are each independently CH, N or O, providing        that only zero, one or two of W⁵, W⁶, W⁷ and W⁸ are N or O;    -   W⁹ is N, O or CH₂    -   W¹⁰ is C or N;    -   W¹¹, W¹² and W¹³ are each independently CH, N or O, providing        that only zero, one or two of W¹¹, W¹² and W¹³ are N or O;    -   W¹⁴, W¹⁵, W¹⁶ and W¹⁷ are each independently CH, N or O,        providing that only zero, one or two of W¹⁴, W¹⁵, W¹⁶ and W¹⁷        are N or O;    -   W¹⁸ is N, O or CH₂        -   W¹⁹ is C or N; and    -   W²⁰, W²¹, W²² and W²³ are each independently CH, N or O,        providing that only zero, one or two of W²⁰, W²¹, W²² and W²³        are N or O.

-   (57) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein    -   each q² is independently 0 or 1;    -   each q³ is independently 0, 1 or 2;    -   v² and v³ are each independently 1 or 2;    -   W², W³ and W⁴ are each independently CH or N, providing that        only zero, one or two of W², W³ and W⁴ are N;    -   W⁵, W⁶, W⁷ and W⁸ are each independently CH or N, providing that        only zero, one or two of W⁵, W⁶, W⁷ and W⁸ are N;    -   W⁹ is N, O or CH₂    -   W¹⁰ is C or N;    -   W¹¹, W¹² and W¹³ are each independently CH or N, providing that        only zero, one or two of W¹¹, W¹² and W¹³ are N;    -   W¹⁴, W¹⁵, W¹⁶ and W¹⁷ are each independently CH or N, providing        that only zero, one or two of W¹⁴, W¹⁵, W¹⁶ and W¹⁷ are N;    -   W¹⁸ is N, O or CH₂    -   W¹⁹ is C or N;    -   W²⁰, W²¹, W²² and W²³ are each independently CH or N, providing        that only zero, one or two of W²⁰, W²¹, W²² and W²³ are N; and    -   each R^(13a) is independently selected from the group consisting        of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any        (1-3C)alkyl and (1-3C)alkoxy in R^(13a) is optionally        substituted with one or more groups independently selected from        the group consisting of hydroxy and halo.

-   (58) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein any of the above rings is optionally substituted with 1,        2 or 3 R¹³.

-   (59) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein each q² is independently 0 or 1 and each q³ is        independently 0, 1 or 2.

-   (60) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein    -   each q² is independently 0 or 1 and each q³ is independently 0,        1 or 2; and    -   each R^(13a) is independently selected from the group consisting        of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any        (1-3C)alkyl and (1-3C)alkoxy in R^(13a) is optionally        substituted with one or more groups independently selected from        the group consisting of hydroxy and halo.

-   (61) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form the following ring    system:

-   -   wherein        -   v² is 1 or 2;        -   ring A is a benzene ring or a 5-6 membered heteroaromatic            ring; and        -   any ring is optionally substituted with one or two R¹³.

-   (62) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form the following ring    system:

-   -   wherein        -   v² is 1 or 2;    -   ring A is a benzene ring or a 5-6 membered heteroaromatic ring        containing 1, 2 or 3 heteroatoms independently selected from N        and O;    -   each R^(13a) is independently selected from the group consisting        of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any        (1-3C)alkyl and (1-3C)alkoxy in R^(13a) is optionally        substituted with one or more groups independently selected from        the group consisting of hydroxy and halo;    -   each q² is independently 0, 1 or 2; and    -   each q³ is independently 0 or 1.

-   (63) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form the following ring    system:

-   -   wherein    -   each q² is independently 0 or 1;    -   each q³ is independently 0, 1 or 2;    -   v³ is independently 1 or 2;    -   W⁵, W⁶, W⁷ and W⁸ are each independently CH or N, providing that        only zero, one or two of W⁴, W⁵, W⁶ and W⁷ are N; and    -   each R^(13a) is independently selected from the group consisting        of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any        (1-3C)alkyl and (1-3C)alkoxy in R^(13a) is optionally        substituted with one or more groups independently selected from        the group consisting of hydroxy and halo.

-   (64) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein v³ is independently 1 or 2; and    -   any ring is optionally substituted with one or two R¹³.

-   (65) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein        -   each q³ is independently 0 or 1;        -   each q³ is independently 0, 1 or 2; and        -   v³ is independently 1 or 2.

-   (66) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein    -   each q³ is independently 0 or 1;    -   each q³ is independently 0, 1 or 2;    -   v³ is independently 1 or 2; and    -   each R^(13a) is independently selected from the group consisting        of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any        (1-3C)alkyl and (1-3C)alkoxy in R^(13a) is optionally        substituted with one or more groups independently selected from        the group consisting of hydroxy and halo.

-   (67) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form the following ring    system:

-   -   wherein        -   each q³ is independently 0 or 1;        -   each q³ is independently 0, 1 or 2; and        -   v³ is independently 1 or 2.

-   (68) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form the following ring    system:

-   -   wherein    -   each q³ is independently 0 or 1;    -   each q³ is independently 0, 1 or 2;    -   v³ is independently 1 or 2; and    -   each R^(13a) is independently selected from the group consisting        of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any        (1-3C)alkyl and (1-3C)alkoxy in R^(13a) is optionally        substituted with one or more groups independently selected from        the group consisting of hydroxy and halo.

-   (69) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein any of the above rings is optionally substituted with 1,        2 or 3 R¹³.

-   (70) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein    -   each q² is independently 0 or 1 and each q³ is independently 0,        1 or 2.

-   (71) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein    -   each q² is independently 0 or 1 and each q³ is independently 0,        1 or 2; and    -   each R^(13a) is independently selected from the group consisting        of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, wherein any        (1-3C)alkyl and (1-3C)alkoxy in R^(13a) is optionally        substituted with one or more groups independently selected from        the group consisting of hydroxy and halo.

-   (72) Each R¹³ is independently selected from the group consisting of    halogen, oxo, epoxy and a group -L¹-X¹-Q¹ (as defined hereinbefore    or in any one of paragraphs (80) to (101) or (126) to (135) below).

-   (73) Each R¹³ is independently selected from the group consisting of    halogen, epoxy and a group -L¹-X¹-Q¹ (as defined hereinbefore or in    any one of paragraphs (97) to (101) or (133) to (135) below).

-   (74) Each R¹³ is independently selected from the group consisting of    fluoro, bromo, epoxy and a group -L¹-X¹-Q¹ (as defined hereinbefore    or in any one of paragraphs (99) to (101) or (134) to (135) below).

-   (75) Each R¹³ is independently selected from the group consisting of    fluoro and a group -L¹-X¹-Q¹ (as defined hereinbefore or in any one    of paragraphs (100) or (101) or (134) to (135) below).

-   (76) Each R^(13a) is independently selected from the group    consisting of oxo, hydroxy, halo, (1-2C)alkyl and (1-2C)alkoxy,    wherein any (1-2C)alkyl and (1-2C)alkoxy in R^(13a) is optionally    substituted with one or more groups independently selected from the    group consisting of hydroxy and halo.

-   (77) Each R^(13a) is independently selected from the group    consisting of oxo, hydroxy, halo, (1-2C)alkyl and methoxy, wherein    any (1-2C)alkyl in R^(13a) is optionally substituted with one or    more groups independently selected from the group consisting of    hydroxy and halo.

-   (78) Each R^(13a) is independently selected from the group    consisting of oxo, hydroxy, (1-2C)alkyl, —CH₂OH, —CH₂F, —CHF₂, —CF₃    and methoxy.

-   (79) Each R^(13a) is independently selected from the group    consisting of oxo, hydroxy, (1-2C)alkyl and —CH₂OH,

-   (80) L¹ is absent or (1-2C)alkylene.

-   (81) L¹ is absent or methylene.

-   (82) L¹ is absent.

-   (83) L¹ is methylene.

-   (84) X¹ is absent or is selected from the group consisting of —O—,    —C(O)—, —C(O)—O—, —O—C(O)—, —S(O)₀₋₂—, —C(O)—N(R¹⁴)—, —N(R¹⁴)—C(O)—,    or —NR¹⁴—, where R¹⁴ is, at each occurrence, independently selected    from the group consisting of hydrogen, hydroxy, cyano, (1-4C)alkyl    and (2-4C)alkenyl, where any (1-4C)alkyl or (2-4C)alkenyl in R¹⁴ is    independently optionally substituted with one or more groups    selected from the group consisting of halogen and hydroxy.

-   (85) X¹ is absent or is selected from the group consisting of —O—,    —C(O)—, —C(O)—O—, —N(R¹⁴)—C(O)—, or —NR¹⁴—, where R¹⁴ is, at each    occurrence, independently selected from the group consisting of    hydrogen, cyano, (1-4C)alkyl and (2-4C)alkenyl, where any    (1-4C)alkyl or (2-4C)alkenyl in R¹⁴ is independently optionally    substituted with one or more groups selected from the group    consisting of halogen and hydroxy.

-   (86) X¹ is absent or is selected from the group consisting of —O—,    —C(O)—, —C(O)—O—, —N(R¹⁴)—C(O)—, or —NR¹⁴—, where R¹⁴ is, at each    occurrence, independently selected from the group consisting of    hydrogen, cyano, (1-4C)alkyl and (2-4C)alkenyl, where any    (1-4C)alkyl or (2-4C)alkenyl in R¹⁴ is independently optionally    substituted with one, two or three groups selected from the group    consisting of fluoro, chloro and hydroxy.

-   (87) X¹ is absent or is selected from the group consisting of —O—,    —C(O)—, —C(O)—O—, —N(R¹⁴)—C(O)—, or —NR¹⁴—, where R¹⁴ is, at each    occurrence, independently selected from the group consisting of    hydrogen, cyano, (1-4C)alkyl and (2-4C)alkenyl.

-   (88) X¹ is absent or is selected from the group consisting of —O—,    —C(O)—, —C(O)—O—, —N(R¹⁴)—C(O)—, or —NR¹⁴—, where R¹⁴ is, at each    occurrence, independently selected from the group consisting of    hydrogen, cyano and (1-2C)alkyl.

-   (89) X¹ is absent or is selected from the group consisting of —O—,    —C(O)—O— and —NR¹⁴—, where R¹⁴ is, at each occurrence, independently    selected from the group consisting of hydrogen and (1-2C)alkyl.

-   (90) Q¹ is selected from the group consisting of hydrogen,    (1-6C)alkyl, (2-6C)alkenyl, aryl, heterocyclyl and heteroaryl,    wherein any (1-6C)alkyl, (2-6C)alkenyl, aryl, heterocyclyl or    heteroaryl in Q¹ is optionally substituted with one or more groups    R¹⁵.

-   (91) Q¹ is selected from the group consisting of hydrogen,    (1-4C)alkyl, (2-4C)alkenyl, phenyl, 5-6 membered heterocyclyl and    5-6 membered heteroaryl, wherein any (1-4C)alkyl, (2-4C)alkenyl,    phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl in Q¹    is optionally substituted with one or more groups R¹⁵.

-   (92) Q¹ is selected from the group consisting of hydrogen,    (1-4C)alkyl, (2-4C)alkenyl, phenyl, 5-6 membered heterocyclyl and    5-6 membered heteroaryl, wherein any (1-4C)alkyl, (2-4C)alkenyl,    phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl in Q¹    is optionally substituted with one, two or three groups R¹⁵.

-   (93) Q¹ is selected from the group consisting of hydrogen,    (1-4C)alkyl, (2-4C)alkenyl, phenyl, 5-6 membered heterocyclyl    containing 1 or 2 heteroatoms independently selected from N and O,    and 5-6 membered heteroaryl containing 1 or 2 heteroatoms    independently selected from N and O, wherein any (1-4C)alkyl,    (2-4C)alkenyl, phenyl, 5-6 membered heterocyclyl or 5-6 membered    heteroaryl in Q¹ is optionally substituted with one, two or three    groups R¹⁵.

-   (94) Q¹ is selected from the group consisting of hydrogen,    (1-4C)alkyl and 5-6 membered heterocyclyl containing 1 or 2    heteroatoms independently selected from N and O, wherein any    (1-4C)alkyl or 5-6 membered heterocyclyl in Q¹ is optionally    substituted with one or more groups R¹⁵.

-   (95) Q¹ is selected from the group consisting of hydrogen,    (1-2C)alkyl and piperazinyl wherein any (1-2C)alkyl or piperazinyl    in Q¹ is optionally substituted with one or more groups R¹⁵.

-   (96) Q¹ is selected from the group consisting of hydrogen,    (1-2C)alkyl and piperazinyl wherein any (1-2C)alkyl or piperazinyl    in Q¹ is optionally substituted with one or two groups R¹⁵.

-   (97) L¹ is absent or (1-2C)alkylene;    -   X¹ is absent or is selected from the group consisting of —O—,        —C(O)—, —C(O)—O—, —O—C(O)—, —S(O)₀₋₂—, —C(O)—N(R¹⁴)—,        —N(R¹⁴)—C(O)—, or —NR¹⁴—, where R¹⁴ is, at each occurrence,        independently selected from the group consisting of hydrogen,        hydroxy, cyano, (1-4C)alkyl and (2-4C)alkenyl, where any        (1-4C)alkyl or (2-4C)alkenyl in R¹⁴ is independently optionally        substituted with one or more groups selected from the group        consisting of halogen and hydroxy; and    -   Q¹ is selected from the group consisting of hydrogen,        (1-6C)alkyl, (2-6C)alkenyl, aryl, heterocyclyl and heteroaryl,        wherein any (1-6C)alkyl, (2-6C)alkenyl, aryl, heterocyclyl or        heteroaryl in Q¹ is optionally substituted with one or more        groups R¹⁵.

-   (98) L¹ is absent or (1-2C)alkylene;    -   X¹ is absent or is selected from the group consisting of —O—,        —C(O)—, —C(O)—O—, —N(R¹⁴)—C(O)—, or —NR¹⁴—, where R¹⁴ is, at        each occurrence, independently selected from the group        consisting of hydrogen, cyano, (1-4C)alkyl and (2-4C)alkenyl,        where any (1-4C)alkyl or (2-4C)alkenyl in R¹⁴ is independently        optionally substituted with one, two or three groups selected        from the group consisting of fluoro, chloro and hydroxy; and    -   Q¹ is selected from the group consisting of hydrogen,        (1-4C)alkyl, (2-4C)alkenyl, phenyl, 5-6 membered heterocyclyl        and 5-6 membered heteroaryl, wherein any (1-4C)alkyl,        (2-4C)alkenyl, phenyl, 5-6 membered heterocyclyl or 5-6 membered        heteroaryl in Q¹ is optionally substituted with one, two or        three groups R¹⁵.

-   (99) L¹ is absent or (1-2C)alkylene;    -   X¹ is absent or is selected from the group consisting of —O—,        —C(O)—, —C(O)—O—, —N(R¹⁴)—C(O)—, or —NR¹⁴—, where R¹⁴ is, at        each occurrence, independently selected from the group        consisting of hydrogen, cyano, (1-4C)alkyl and (2-4C)alkenyl;        and    -   Q¹ is selected from the group consisting of hydrogen,        (1-4C)alkyl, (2-4C)alkenyl, phenyl, 5-6 membered heterocyclyl        containing 1 or 2 heteroatoms independently selected from N and        O, and 5-6 membered heteroaryl containing 1 or 2 heteroatoms        independently selected from N and O, wherein any (1-4C)alkyl,        (2-4C)alkenyl, phenyl, 5-6 membered heterocyclyl or 5-6 membered        heteroaryl in Q¹ is optionally substituted with one, two or        three groups R¹⁵.

-   (100) L¹ is absent or (1-2C)alkylene;    -   X¹ is absent or is selected from the group consisting of —O—,        —C(O)—, —C(O)—O—, —N(R¹⁴)—C(O)—, or —NR¹⁴—, where R¹⁴ is, at        each occurrence, independently selected from the group        consisting of hydrogen, cyano and (1-2C)alkyl; and    -   Q¹ is selected from the group consisting of hydrogen,        (1-2C)alkyl and piperazinyl wherein any (1-2C)alkyl or        piperazinyl in Q¹ is optionally substituted with one or more        groups R¹⁵.

-   (101) L¹ is absent or (1-2C)alkylene;    -   X¹ is absent or is selected from the group consisting of —O—,        —C(O)—O— and —NR¹⁴—, where R¹⁴ is, at each occurrence,        independently selected from the group consisting of hydrogen and        (1-2C)alkyl; and    -   Q¹ is selected from the group consisting of hydrogen,        (1-2C)alkyl and piperazinyl wherein any (1-2C)alkyl or        piperazinyl in Q¹ is optionally substituted with one or two        groups R¹⁵.

-   (102) Each R¹⁵ is independently selected from the group consisting    of hydroxy, cyano, oxo, halogen, (1-3C)alkyl, (1-3C)alkoxy,    —NR^(15a)R^(15b), —C(O)—R^(15a), —C(O)—OR^(15a), —O—C(O)—R^(15a),    —C(O)—NR^(15a)R^(15b) and —N(R^(15b))C(O)—R^(15a), wherein R^(15a)    and R^(15b) are each independently hydrogen or (1-3C)alkyl, and    wherein any (1-3C)alkyl moiety present in a R^(15a) or R^(15b) group    is optionally further substituted by one or more substituents    independently selected from hydroxy, cyano, halogen,    —NR^(15c)R^(15d), —C(O)—NR^(15c)R^(15d) and —N(R^(15c))C(O)—R^(15d)    wherein R^(15c), and R^(15d) are both independently selected from    hydrogen and (1-2C)alkyl.

-   (103) Each R¹⁵ is independently selected from the group consisting    of hydroxy, cyano, oxo, halogen, (1-3C)alkyl, (1-3C)alkoxy,    —NR^(15a)R^(15b), —C(O)—NR^(15a)R^(15b) and —N(R^(15b))C(O)—R^(15a),    wherein R^(15a) and R^(15b) are each independently hydrogen or    (1-3C)alkyl, and wherein any (1-3C)alkyl moiety present in a R^(15a)    or R^(15b) group is optionally further substituted by one or more    substituents independently selected from hydroxy, halogen and    —NR^(15c)R^(15d) wherein R^(15c) and R^(15d) are both independently    selected from hydrogen and (1-2C)alkyl.

-   (104) Each R¹⁵ is independently selected from the group consisting    of hydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy,    —NR^(15a)R^(15b) and —C(O)—NR^(15a)R^(15b), wherein R^(15a) and    R^(15b) are each independently hydrogen or (1-3C)alkyl.

-   (105) Each R¹⁵ is independently selected from the group consisting    of hydroxy, cyano, halogen, (1-3C)alkyl and —C(O)—NR^(15a)R^(15b),    wherein R^(15a) and R^(15b) are each independently hydrogen or    methyl.

-   (106) Each R¹⁵ is independently selected from the group consisting    of hydroxy, halogen, (1-3C)alkyl and —C(O)—NR^(15a)R^(15b), wherein    R^(15a) and R^(15b) are each independently hydrogen or methyl.

-   (107) Each R¹⁵ is independently selected from the group consisting    of hydroxy, (1-3C)alkyl and —C(O)—NR^(15a)R^(15b), wherein R^(15a)    and R^(15b) are each independently hydrogen or methyl.

-   (108) Each R¹⁵ is independently selected from the group consisting    of hydroxy, halogen and (1-3C)alkyl.

-   (109) R⁶ is (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl or a 4- to    7-membered heterocyclyl ring comprising one heteroatom selected from    N, O or S, or a group having a structure according to formula (A)    shown below:

-   -   wherein n, R⁷ and R⁸ are each as defined herein.

-   (110) R⁶ is (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or a 4- to    7-membered heterocyclyl ring comprising one heteroatom selected from    N, O or S, or a group having a structure according to formula (A)    shown below:

-   -   wherein n, R⁷ and R⁸ are each as defined herein.

-   (111) R⁶ is (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or a 5- or    6-membered heterocyclyl ring comprising one heteroatom selected from    O or S, or a group having a structure according to formula (A) shown    below:

-   -   wherein n, R⁷ and R⁸ are each as defined herein.

-   (112) R⁶ is (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or    tetrahydropyran, or a group having a structure according to    formula (A) shown below:

-   -   wherein n, R⁷ and R⁸ are each as defined herein.

-   (113) R⁶ is (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl, or a    group having a structure according to formula (A) shown below:

-   -   wherein n, R⁷ and R⁸ are each as defined herein.

-   (114) R⁶ is a group having a structure according to formula (A)    shown below:

-   -   wherein n, R⁷ and R⁸ are each as defined herein.

-   (115) R⁶ is (1-6C)alkyl, (3-8C)cycloalkyl,    (3-8C)cycloalkyl(1-2C)alkyl or a 4- to 7-membered heterocyclyl ring    comprising one heteroatom selected from N, O or S, or a group having    a structure according to formula (A) shown below:

-   -   wherein n, R⁷ and R⁸ are each as defined herein.

-   (116) R⁶ is (1-6C)alkyl, (3-6C)cycloalkyl,    (3-6C)cycloalkyl(1-2C)alkyl or a 4- to 7-membered heterocyclyl ring    comprising one heteroatom selected from N, O or S, or a group having    a structure according to formula (A) shown below:

-   -   wherein n, R⁷ and R⁸ are each as defined herein.

-   (117) R⁶ is (1-4C)alkyl, (3-6C)cycloalkyl,    (3-6C)cycloalkyl(1-2C)alkyl or a 5- or 6-membered heterocyclyl ring    comprising one heteroatom selected from O or S, or a group having a    structure according to formula (A) shown below:

-   -   wherein n, R⁷ and R⁸ are each as defined herein.

-   (118) R⁶ is (1-3C)alkyl, (3-6C)cycloalkyl,    (3-6C)cycloalkyl(1-2C)alkyl or tetrahydropyran, or a group having a    structure according to formula (A) shown below:

-   -   wherein n, R⁷ and R⁸ are each as defined herein.

-   (119) R⁶ is (1-2C)alkyl, (3-6C)cycloalkyl or    (3-6C)cycloalkyl(1-2C)alkyl, or a group having a structure according    to formula (A) shown below:

-   -   wherein n, R⁷ and R⁸ are each as defined herein.

-   (120) R⁶ is methyl.

-   (121) R⁶ is ethyl.

-   (122) R¹¹ and R¹² are linked, such that, together with the nitrogen    atom to which they are attached, they form any one of the following    ring systems:

-   -   wherein any of the above rings is optionally substituted with 1,        2 or 3 R¹³.

-   (123) Each R¹³ is independently selected from the group consisting    of halogen, cyano, oxo, epoxy and a group -L¹-X¹-Q¹ (as defined    anywhere herein).

-   (124) Each R¹³ is independently selected from the group consisting    of halogen, cyano, epoxy and a group -L¹-X¹-Q¹ (as defined anywhere    herein or in any one of paragraphs (97) to (101) or (133) to (135)).

-   (125) Each R¹³ is independently selected from the group consisting    of fluoro, bromo, cyano, epoxy and a group -L¹-X¹-Q¹ (as defined    anywhere herein or in any one of paragraphs (99) to (101) or (133)    to (135)).

-   (126) X¹ is absent or is selected from the group consisting of —O—,    —C(O)—, —C(O)—O—, —O—C(O)—, —S(O)₀₋₂—, —C(O)—N(R¹⁴)—, —N(R¹⁴)—C(O)—,    or —NR¹⁴—, where R¹⁴ is, at each occurrence, independently selected    from the group consisting of hydrogen, hydroxy, cyano, (1-4C)alkyl    and (2-4C)alkenyl, where any (1-4C)alkyl or (2-4C)alkenyl in R¹⁴ is    independently optionally substituted with one or more groups    selected from the group consisting of halogen and hydroxy.

-   (127) X¹ is absent or is selected from the group consisting of —O—,    —C(O)—, —C(O)—O—, —C(O)—N(R¹⁴)—, —N(R¹⁴)—C(O)—, or —NR¹⁴—, where R¹⁴    is, at each occurrence, independently selected from the group    consisting of hydrogen, cyano and (1-2C)alkyl.

-   (128) X¹ is absent or is selected from the group consisting of —O—,    —C(O)—O—, —C(O)—N(R¹⁴)— and —N(R¹⁴)—C(O)—, —NR¹⁴—, where R¹⁴ is, at    each occurrence, independently selected from the group consisting of    hydrogen and (1-2C)alkyl.

-   (129) Q¹ is selected from the group consisting of hydrogen,    (1-6C)alkyl, (2-6C)alkenyl, aryl, aryl(1-3C)alkyl, heterocyclyl,    heterocyclyl(1-3C)alkyl, heteroaryl and heteroaryl(1-3C)alkyl,    wherein any (1-6C)alkyl, (2-6C)alkenyl, aryl, aryl(1-3C)alkyl,    heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl or    heteroaryl(1-3C)alkyl in Q¹ is optionally substituted with one or    more groups R¹⁵.

-   (130) Q¹ is selected from the group consisting of hydrogen,    (1-4C)alkyl, (2-4C)alkenyl, aryl, aryl(1-2C)alkyl, heterocyclyl,    heterocyclyl(1-2C)alkyl, heteroaryl and heteroaryl(1-2C)alkyl,    wherein any (1-4C)alkyl, (2-4C)alkenyl, aryl, aryl(1-2C)alkyl,    heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl or    heteroaryl(1-2C)alkyl in Q¹ is optionally substituted with one or    more groups R¹⁵.

-   (131) Q¹ is selected from the group consisting of hydrogen,    (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1-2C)alkyl, 4-6 membered    heterocyclyl, 4-6 membered heterocyclyl(1-2C)alkyl, 4-6 membered    heteroaryl and 4-6 membered heteroaryl(1-2C)alkyl, wherein any    (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1-2C)alkyl, 4-6 membered    heterocyclyl, 4-6 membered heterocyclyl(1-2C)alkyl, 4-6 membered    heteroaryl or 4-6 membered heteroaryl(1-2C)alkyl in Q¹ is optionally    substituted with one or more groups R¹⁵.

-   (132) Q¹ is selected from the group consisting of hydrogen,    (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1C)alkyl, 4-6 membered    heterocyclyl, 4-6 membered heterocyclyl(1C)alkyl, 4-6 membered    heteroaryl and 4-6 membered heteroaryl(1C)alkyl, wherein any    (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1C)alkyl, 4-6 membered    heterocyclyl, 4-6 membered heterocyclyl(1C)alkyl, 4-6 membered    heteroaryl or 4-6 membered heteroaryl(1C)alkyl in Q¹ is optionally    substituted with one or more groups R¹⁵.

-   (133) L¹ is absent or (1-2C)alkylene;    -   X¹ is absent or is selected from the group consisting of —O—,        —C(O)—, —C(O)—O—, —O—C(O)—, —S(O)₀₋₂—, —C(O)—N(R¹⁴)—,        —N(R¹⁴)—C(O)—, or —NR¹⁴—, where R¹⁴ is, at each occurrence,        independently selected from the group consisting of hydrogen,        hydroxy, cyano, (1-4C)alkyl and (2-4C)alkenyl, where any        (1-4C)alkyl or (2-4C)alkenyl in R¹⁴ is independently optionally        substituted with one or more groups selected from the group        consisting of halogen and hydroxy; and    -   Q¹ is selected from the group consisting of hydrogen,        (1-6C)alkyl, (2-6C)alkenyl, aryl, aryl(1-3C)alkyl, heterocyclyl,        heterocyclyl(1-3C)alkyl, heteroaryl and heteroaryl(1-3C)alkyl,        wherein any (1-6C)alkyl, (2-6C)alkenyl, aryl, aryl(1-3C)alkyl,        heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl or        heteroaryl(1-3C)alkyl in Q¹ is optionally substituted with one        or more groups R¹⁵.

-   (134) L¹ is absent or (1-2C)alkylene;    -   X¹ is absent or is selected from the group consisting of —O—,        —C(O)—, —C(O)—O—, —C(O)—N(R¹⁴)—, —N(R¹)—C(O)—, or —NR¹⁴—, where        R¹⁴ is, at each occurrence, independently selected from the        group consisting of hydrogen, cyano and (1-2C)alkyl; and    -   Q¹ is selected from the group consisting of hydrogen,        (1-4C)alkyl, (2-4C)alkenyl, aryl, aryl(1-2C)alkyl, heterocyclyl,        heterocyclyl(1-2C)alkyl, heteroaryl and heteroaryl(1-2C)alkyl,        wherein any (1-4C)alkyl, (2-4C)alkenyl, aryl, aryl(1-2C)alkyl,        heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl or        heteroaryl(1-2C)alkyl in Q¹ is optionally substituted with one        or more groups R¹⁵.

-   (135) L¹ is absent or (1-2C)alkylene;    -   X¹ is absent or is selected from the group consisting of —O—,        —C(O)—O—, —C(O)—N(R¹⁴)— and —N(R¹⁴)—C(O)—, —NR¹⁴—, where R¹⁴ is,        at each occurrence, independently selected from the group        consisting of hydrogen and (1-2C)alkyl; and    -   Q¹ is selected from the group consisting of hydrogen,        (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1C)alkyl, 4-6        membered heterocyclyl, 4-6 membered heterocyclyl(1C)alkyl, 4-6        membered heteroaryl and 4-6 membered heteroaryl(1C)alkyl,        wherein any (1-4C)alkyl, (2-4C)alkenyl, phenyl, phenyl(1C)alkyl,        4-6 membered heterocyclyl, 4-6 membered heterocyclyl(1C)alkyl,        4-6 membered heteroaryl or 4-6 membered heteroaryl(1C)alkyl in        Q¹ is optionally substituted with one or more groups R¹⁵.

Suitably, R¹ and R³ are as defined in any one of numbered paragraphs (3)to (4). Most suitably, R¹ and R³ are as defined in numbered paragraph(4).

Suitably, R² is as defined in numbered paragraph (6).

Suitably, R⁴ is as defined in any one of numbered paragraphs (10) to(17). More suitably, R⁴ is as defined in any one of numbered paragraphs(13) to (17). Most suitably, R⁴ is as defined in any one of numberedparagraphs (15) to (17).

Suitably, R^(5a) is as defined in any one of numbered paragraphs (19) to(20). Most suitably, R^(5a) is as defined in numbered paragraph (20).

Suitably, R^(5b) is as defined in any one of numbered paragraphs (23) to(24). Most suitably, R^(5a) is as defined in numbered paragraph (24).

Suitably, R⁷ is as defined in any one of numbered paragraphs (27) to(29). Most suitably, R⁷ is as defined in numbered paragraph (28).

Suitably, n is as defined in numbered paragraph (30).

Suitably, R⁸ is as defined in any one of numbered paragraphs (34) to(39). More suitably, R⁸ is as defined in any one of numbered paragraphs(36) to (39). Most suitably, R⁸ is as defined in numbered paragraph(39).

Suitably, m¹ is as defined in numbered paragraph (41) or (42). Mostsuitably, m¹ is as defined in numbered paragraph (42).

Suitably, R⁹ is as defined in any one of numbered paragraphs (46) to(50). More suitably, R⁹ is as defined in any one of numbered paragraphs(48) to (50). Most suitably, R⁹ is as defined in numbered paragraph(50).

Suitably, R¹¹ and R¹² are as defined in any one of numbered paragraphs(53) to (71). More suitably, R¹¹ and R¹² are as defined in any one ofnumbered paragraphs (57) to (71). Even more suitably, R¹¹ and R¹² are asdefined in any one of numbered paragraphs (61) to (71). Yet even moresuitably, R¹¹ and R¹² are as defined in any one of numbered paragraphs(64) to (71). Still more suitably, R¹¹ and R¹² are as defined in any oneof numbered paragraphs (67) to (71). Most suitably, R¹¹ and R¹² are asdefined in any one of numbered paragraphs (70) to (71).

Suitably, R¹¹ and R¹² are as defined in numbered paragraph (122).

Suitably, R¹³ is as defined in numbered paragraph (74) or (75).

Suitably, R^(13a) is as defined in any one of numbered paragraphs (78)to (79).

Suitably, L¹ is as defined in any one of numbered paragraphs (81) to(83).

Suitably, X¹ is as defined in any one of numbered paragraphs (86) to(89). More suitably, X¹ is as defined in any one of numbered paragraphs(88) to (89).

Suitably, X¹ is as defined in any one of numbered paragraphs (126) to(128). More suitably, X¹ is as defined in numbered paragraph (128).

Suitably, Q¹ is as defined in any one of numbered paragraphs (93) to(96). More suitably, Q¹ is as defined in any one of numbered paragraphs(95) to (96).

Suitably, Q¹ is as defined in any one of numbered paragraphs (129) to(132). More suitably, Q¹ is as defined in any one of numbered paragraphs(130) to (132). Most suitably, Q¹ is as defined in numbered paragraphs(131) or (132).

Suitably, L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs(99) to (101).

Suitably, L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs(133) to (135). Most suitably, L¹, X¹ and Q¹ are as defined in numberedparagraphs (134) or (135).

Suitably, R¹⁵ is as defined in any one of numbered paragraphs (105) to(108). More suitably, R¹⁵ is as defined in any one of numberedparagraphs (107) to (108).

Suitably, R⁶ is as defined in any one of numbered paragraphs (109) to(114). More suitably, R⁶ is as defined in any one of numbered paragraphs(111), (112), (113) or (114).

Suitably, R⁶ is as defined in any one of numbered paragraphs (115) to(121). More suitably, R⁶ is as defined in any one of numbered paragraphs(118), (119), (120) or (121).

In a particular group of compounds of the invention, compounds have astructure according to formula I-I (which is a sub-definition of formulaI), or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

wherein n, R², R⁴, R⁷, R⁸, R¹⁰, and any associated subgroups, are asdefined in any of the numbered paragraphs appearing hereinbefore.

In an embodiment of the compounds of formula I-I, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (10) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (31) to (39);R¹¹ and R¹² are as defined in any one of numbered paragraphs (53) to(71); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-I, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (34) to (39);R⁹ is as defined in any one of numbered paragraphs (46) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (53) to(71);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula 1-1, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (57) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula 1-1, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (61) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (93);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula 1-1, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (64) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula 1-1, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (64) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula 1-1, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula 1-1, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula 1-1, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹¹ and R¹² are as defined in any one of numbered paragraphs (70) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula 1-1, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹¹ and R¹² are as defined in numbered paragraph (70);R¹³ is as defined in numbered paragraph (74);R^(13a) is as defined in numbered paragraph (78);L¹, X¹ and Q¹ are as defined in numbered paragraph (99);R¹⁵ is as defined in numbered paragraph (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula 1-1, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71) or (122);R¹³ is as defined in numbered paragraph (74), (75) or (123) to (125);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101) or (133) to (135);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula 1-1, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹¹ and R¹² are as defined in any one of numbered paragraphs (70) to(71) or (122);R¹³ is as defined in numbered paragraph (74), (75) or (124) to (125);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101) or (134) to (135);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula 1-1, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹¹ and R¹² are as defined in numbered paragraph (122);R¹³ is as defined in numbered paragraph (74) or (124);R^(13a) is as defined in numbered paragraph (78);L¹, X¹ and Q¹ are as defined in numbered paragraph (134) or (135);R¹⁵ is as defined in numbered paragraph (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore. In a particular group of compounds of theinvention, compounds have a structure according to formula I-II (whichis a sub-definition of formula I), or a pharmaceutically acceptablesalt, hydrate and/or solvate thereof:

wherein n, m¹, R¹, R², R³, R⁴, R⁷, R⁹, R¹⁰ and any associated subgroupsare as defined in any of the numbered paragraphs appearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (10) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R¹¹ and R¹² are as defined in any one of numbered paragraphs (53) to(71); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (46) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (53) to(71);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (57) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (61) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (93);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (64) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (64) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (70) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in numbered paragraphs (3);m¹ is as defined in numbered paragraph (41);R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R⁹ is as defined in numbered paragraph (48);R¹¹ and R¹² are as defined in numbered paragraph (70);R¹³ is as defined in numbered paragraph (74);R^(13a) is as defined in numbered paragraph (78);L¹, X¹ and Q¹ are as defined in numbered paragraph (99);R¹⁵ is as defined in numbered paragraph (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71) or (122);R¹³ is as defined in any one of numbered paragraphs (74), (75) or (123)to (125);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101) or (133) to (135);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (70) to(71) or (122);R¹³ is as defined in any one of numbered paragraphs (74), (75) or (124)to (125);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101) or (134) to (135);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-II, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in numbered paragraph (3);m¹ is as defined in numbered paragraph (41);R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R⁹ is as defined in numbered paragraphs (48);R¹¹ and R¹² are as defined in numbered paragraph (122);R¹³ is as defined in numbered paragraph (74) or (123);R^(13a) is as defined in numbered paragraph (78);L¹, X¹ and Q¹ are as defined in numbered paragraph (134) or (135);R¹⁵ is as defined in numbered paragraph (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula I-III (which is a sub-definition offormula I), or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

wherein n, m¹, R², R⁴, R⁷, R⁹, R¹⁰ and any associated subgroups are asdefined in any of the numbered paragraphs appearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (10) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R¹¹ and R¹² are as defined in any one of numbered paragraphs (53) to(71); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (46) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (53) to(71);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (57) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (61) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (93);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (64) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (64) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (70) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41);R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R⁹ is as defined in numbered paragraph (48);R¹¹ and R¹² are as defined in numbered paragraph (70);R¹³ is as defined in numbered paragraph (74);R^(13a) is as defined in numbered paragraph (78);L¹, X¹ and Q¹ are as defined in numbered paragraph (99);R¹⁵ is as defined in numbered paragraph (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71) or (122);R¹³ is as defined in numbered paragraph (74), (75) or (123) to (125);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101) or (133) to (135);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (70) to(71) or (122);R¹³ is as defined in numbered paragraph (74), (75) or (124) to (125);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101) or (134) to (135);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-III, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41);R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R⁹ is as defined in numbered paragraph (48);R¹¹ and R¹² are as defined in numbered paragraph (122);R¹³ is as defined in numbered paragraph (74) or (123);R^(13a) is as defined in numbered paragraph (78);L¹, X¹ and Q¹ are as defined in numbered paragraph (134) or (135);R¹⁵ is as defined in numbered paragraph (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula I-IV (which is a sub-definition offormula I), or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

whereinR¹⁰ is —NR¹¹R¹² and R¹¹ and R¹² are as defined in numbered paragraph(53); and n, R², R⁴, R⁷ and R⁸, and any associated subgroups, are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula I-V (which is a sub-definition of formulaI), or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

whereinR¹⁰ is —NR¹¹R¹² and R¹¹ and R¹² are as defined in numbered paragraph(56); andn, R², R⁴, R⁷ and R⁸, and any associated subgroups, are as defined inany of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula I-VI (which is a sub-definition offormula I), or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

whereinR¹⁰ is —NR¹¹R¹² and R¹¹ and R¹² are as defined in numbered paragraph(65) or (66); andn, R², R⁴, R⁷ and R⁸, and any associated subgroups, are as defined inany of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula I-VII (which is a sub-definition offormula I), or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

whereinR¹⁰ is —NR¹¹R¹² and R¹¹ and R¹² are as defined in numbered paragraph(68); and n, R², R⁴, R⁷ and R⁸, and any associated subgroups, are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula I-VIII (which is a sub-definition offormula I), or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

whereinR¹⁰ is —NR¹¹R¹² and R¹¹ and R¹² are as defined in numbered paragraph(70) or (71); andn, R², R⁴, R⁷ and R⁸, and any associated subgroups, are as defined inany of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula i-Villa (which is a sub-definition offormula I), or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

whereinR¹⁰ is —NR¹¹R¹² and R¹¹ and R¹² are as defined in numbered paragraph(122); andn, R², R⁴, R⁷ and R⁸, and any associated subgroups, are as defined inany of the numbered paragraphs appearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII orI-VIII, or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (10) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (31) to (39); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII orI-VIII, or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (34) to (39);R⁹ is as defined in any one of numbered paragraphs (46) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII orI-VIII, or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII orI-VIII, or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (93);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII orI-VIII, or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII orI-VIII, or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII orI-VIII, or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII orI-VIII, or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹³ is as defined in numbered paragraph (74) or (75);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII orI-VIII, or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹³ is as defined in numbered paragraph (74) or (75);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII orI-VIII, or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹³ is as defined in numbered paragraph (74);L¹, X¹ and Q¹ are as defined in numbered paragraph (100);R¹⁵ is as defined in any one of numbered paragraphs (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII orI-VIII, or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (17);R⁷ is as defined in numbered paragraph (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹³ is as defined in numbered paragraph (75);L¹, X¹ and Q¹ are as defined in numbered paragraph (101);R¹⁵ is as defined in any one of numbered paragraphs (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII,I-VIII or I-VIIIa, or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹³ is as defined in numbered paragraph (74), (75) or (123) to (125);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101) or (133) to (135);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII,I-VIII or I-VIIIa, or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹³ is as defined in numbered paragraph (74) or (123);L¹, X¹ and Q¹ are as defined in numbered paragraph (100) or (134);R¹⁵ is as defined in any one of numbered paragraphs (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IV, I-V, I-VI, I-VII,I-VIII or I-VIIIa, or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (17);R⁷ is as defined in numbered paragraph (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹³ is as defined in numbered paragraph (75) or (125);L¹, X¹ and Q¹ are as defined in numbered paragraph (134) or (135);R¹⁵ is as defined in any one of numbered paragraphs (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula I-IX (which is a sub-definition offormula I), or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

whereinR¹⁰ is —NR¹¹R¹² and R¹¹ and R¹² are as defined in numbered paragraph(56); andn, m¹, R¹, R², R³, R⁴, R⁷ and R⁹, and any associated subgroups, are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula I-X (which is a sub-definition of formulaI), or a pharmaceutically acceptable salt, hydrate and/or solvatethereof:

whereinR¹⁰ is —NR¹¹R¹² and R¹¹ and R¹² are as defined in numbered paragraph(68); andn, m¹, R¹, R², R³, R⁴, R⁷ and R⁹, and any associated subgroups, are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula I-Xa (which is a sub-definition offormula I), or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

whereinR¹⁰ is —NR¹¹R¹² and R¹¹ and R¹² are as defined in numbered paragraph(122); andn, m¹, R¹, R², R³, R⁴, R⁷ and R⁹, and any associated subgroups, are asdefined in any of the numbered paragraphs appearing hereinbefore.

In an embodiment of the compounds of formula I-IX or I-X, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (10) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX or I-X, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (46) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX or I-X, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX or I-X, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (93);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX or I-X, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX or I-X, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX or I-X, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX or I-X, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R¹³ is as defined in numbered paragraph (74) or (75);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX or I-X, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R¹³ is as defined in numbered paragraph (74) or (75);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX or I-X, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in paragraph (3);m¹ is as defined in numbered paragraph (41);R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R¹³ is as defined in numbered paragraph (74);L¹, X¹ and Q¹ are as defined in numbered paragraph (100);R¹⁵ is as defined in numbered paragraph (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX or I-X, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in paragraph (4);m¹ is as defined in numbered paragraph (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (17);R⁷ is as defined in numbered paragraph (29);n is as defined in numbered paragraph (30);R¹³ is as defined in numbered paragraph (75);L¹, X¹ and Q¹ are as defined in numbered paragraph (101);R¹⁵ is as defined in numbered paragraph (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX, I-X or I-Xa, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in any one of numbered paragraphs (3) to (4);m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R¹³ is as defined in numbered paragraph (74), (75) or (123) to (125);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101) or (133) to (135);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX, I-X or I-Xa, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in paragraph (3);m¹ is as defined in numbered paragraph (41);R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R¹³ is as defined in numbered paragraph (74) or (123);L¹, X¹ and Q¹ are as defined in numbered paragraph (100) or (134);R¹⁵ is as defined in numbered paragraph (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-IX, I-X or I-Xa, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R¹ and R³ are as defined in paragraph (4);m¹ is as defined in numbered paragraph (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (17);R⁷ is as defined in numbered paragraph (29);n is as defined in numbered paragraph (30);R¹³ is as defined in numbered paragraph (75) or (124);L¹, X¹ and Q¹ are as defined in numbered paragraph (134) or (135);R¹⁵ is as defined in numbered paragraph (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula I-XI (which is a sub-definition offormula I), or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

whereinR¹⁰ is —NR¹¹R¹² and R¹¹ and R¹² are as defined in numbered paragraph(56); andn, m¹, R², R⁴, R⁷ and R⁹, and any associated subgroups, are as definedin any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula I-XII (which is a sub-definition offormula I), or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

whereinR¹⁰ is —NR¹¹R¹² and R¹¹ and R¹² are as defined in numbered paragraph(68); andn, m¹, R², R⁴, R⁷ and R⁹, and any associated subgroups, are as definedin any of the numbered paragraphs appearing hereinbefore.

In an embodiment of the compounds of formula I-XI or I-XII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (10) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XI or I-XII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (46) to (50);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XI or I-XII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XI or I-XII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (93);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XI or I-XII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XI or I-XII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XI or I-XII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XI or I-XII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XI or I-XII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41) or (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XI or I-XII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (41);R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R¹³ is as defined in numbered paragraph (74);R^(13a) is as defined in numbered paragraph (78);L¹, X¹ and Q¹ are as defined in numbered paragraph (100);R¹⁵ is as defined in numbered paragraph (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XI or I-XII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

m¹ is as defined in numbered paragraph (42);R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (17);R⁷ is as defined in numbered paragraph (29);n is as defined in numbered paragraph (30);R¹³ is as defined in numbered paragraph (75);R^(13a) is as defined in numbered paragraph (79);L¹, X¹ and Q¹ are as defined in numbered paragraph (101);R¹⁵ is as defined in numbered paragraph (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (109) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (110) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (111) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (112) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (113) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (114) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (115) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (116) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (117) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (118) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (119) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (120) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of formula I, R⁶ is as defined inparagraph (121) above, and R¹, R², R³, R⁴, n, R⁷, R⁸ and R¹⁰ are asdefined in any of the numbered paragraphs appearing hereinbefore.

In a particular group of compounds of the invention, compounds have astructure according to formula I-XIII (which is a sub-definition offormula I), or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof:

wherein R², R⁴, and R¹⁰, and any associated subgroups, are as defined inany of the numbered paragraphs appearing hereinbefore and R⁶ is asdefined in any one of paragraphs (109) to (121) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (109) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (110) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (111) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (112) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (113) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (114) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (115) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (116) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (117) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (118) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (119) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (120) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof, R⁶ isas defined in paragraph (121) above.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (10) to (17);R⁶ is as defined in any one of numbered paragraphs (109) to (114);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (31) to (39);R¹¹ and R¹² are as defined in any one of numbered paragraphs (53) to(71); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁶ is as defined in any one of numbered paragraphs (111) to (114);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (34) to (39);R⁹ is as defined in any one of numbered paragraphs (46) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (53) to(71);R¹³ is as defined in numbered paragraph (74) or (75);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁶ is as defined in any one of numbered paragraphs (112) to (114);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (57) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁶ is as defined in any one of numbered paragraphs (112) to (114);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (61) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (93);X¹ is as defined in any one of numbered paragraphs (86) to (89);Q¹ is as defined in any one of numbered paragraphs (93) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁶ is as defined in any one of numbered paragraphs (112) to (114);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (64) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁶ is as defined in any one of numbered paragraphs (112) to (114);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (64) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89);Q¹ is as defined in any one of numbered paragraphs (95) to (96);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁶ is as defined in any one of numbered paragraphs (112) to (114);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁶ is as defined in any one of numbered paragraphs (113) to (114);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁶ is as defined in any one of numbered paragraphs (113) to (114);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹¹ and R¹² are as defined in any one of numbered paragraphs (70) to(71);R¹³ is as defined in numbered paragraph (74) or (75);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁶ is as defined in numbered paragraph (113);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹¹ and R¹² are as defined in numbered paragraph (70);R¹³ is as defined in numbered paragraph (74);R^(13a) is as defined in numbered paragraph (78);L¹, X¹ and Q¹ are as defined in numbered paragraph (99);R¹⁵ is as defined in numbered paragraph (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (10) to (17);R⁶ is as defined in any one of numbered paragraphs (109) to (121);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (31) to (39);R¹¹ and R¹² are as defined in any one of numbered paragraphs (53) to(71) or (122); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁶ is as defined in any one of numbered paragraphs (111) to (121);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (34) to (39);R⁹ is as defined in any one of numbered paragraphs (46) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (53) to(71) or (122);R¹³ is as defined in numbered paragraph (74), (75) or (123) to (125);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89) or (126)to (128);Q¹ is as defined in any one of numbered paragraphs (93) to (96) or (129)to (132); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁶ is as defined in any one of numbered paragraphs (112) to (121);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (57) to(71) or (122);R¹³ is as defined in numbered paragraph (74), (75), (124) or (125);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89) or (126)to (128);Q¹ is as defined in any one of numbered paragraphs (93) to (96) or (130)to (132); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (13) to (17);R⁶ is as defined in any one of numbered paragraphs (112) to (121);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (61) to(71) or (122);R¹³ is as defined in numbered paragraph (74), (75) or (123);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (86) to (89) or (126)to (128);Q¹ is as defined in any one of numbered paragraphs (93) to (96) or (131)to (132);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (5) or (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁶ is as defined in any one of numbered paragraphs (112) to (114) or(119) to (121);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (64) to(71) or (122);R¹³ is as defined in numbered paragraph (74), (75) or (123);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89) or (127)to (128);Q¹ is as defined in any one of numbered paragraphs (95) to (96) or (131)to (132);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁶ is as defined in any one of numbered paragraphs (112) to (114) or(119) to (121);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (64) to(71) or (122);R¹³ is as defined in numbered paragraph (74), (75) or (123);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹ is as defined in any one of numbered paragraphs (81) to (83);X¹ is as defined in any one of numbered paragraphs (88) to (89) or (127)to (128);Q¹ is as defined in any one of numbered paragraphs (95) to (96) or (131)to (132);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁶ is as defined in any one of numbered paragraphs (112) to (114) or(119) to (121);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in any one of numbered paragraphs (36) to (39);R⁹ is as defined in any one of numbered paragraphs (48) to (50);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71) or (122);R¹³ is as defined in numbered paragraph (74), (75) or (124);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101) or (133) to (135);R¹⁵ is as defined in any one of numbered paragraphs (105) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁶ is as defined in any one of numbered paragraphs (113) to (114) or(120) to (121);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹¹ and R¹² are as defined in any one of numbered paragraphs (67) to(71) or (122);R¹³ is as defined in numbered paragraph (74), (75) or (124);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101) or (133) to (135);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in any one of numbered paragraphs (15) to (17);R⁶ is as defined in any one of numbered paragraphs (113) to (114) or(120) to (121);R⁷ is as defined in any one of numbered paragraphs (27) to (29);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹¹ and R¹² are as defined in any one of numbered paragraphs (70) to(71) or (122);R¹³ is as defined in numbered paragraph (74), (75) or (124);R^(13a) is as defined in any one of numbered paragraphs (78) to (79);L¹, X¹ and Q¹ are as defined in any one of numbered paragraphs (99) to(101) or (133) to (135);R¹⁵ is as defined in any one of numbered paragraphs (107) to (108); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

In an embodiment of the compounds of formula I-XIII, or apharmaceutically acceptable salt, hydrate and/or solvate thereof:

R² is as defined in numbered paragraph (6);R⁴ is as defined in numbered paragraph (15);R⁶ is as defined in numbered paragraph (113);R⁷ is as defined in numbered paragraph (27);n is as defined in numbered paragraph (30);R⁸ is as defined in numbered paragraph (39);R¹¹ and R¹² are as defined in numbered paragraph (122);R¹³ is as defined in numbered paragraph (74) or (125);R^(13a) is as defined in numbered paragraph (78);L¹, X¹ and Q¹ are as defined in numbered paragraph (134) or (135);R¹⁵ is as defined in numbered paragraph (107); andall other groups are as defined in any of the numbered paragraphsappearing hereinbefore.

Particular compounds of the present invention include any of thecompounds exemplified in the present application, or a pharmaceuticallyacceptable salt or solvate thereof, and, in particular, any of thefollowing:

-   [2,4-dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;-   [2-(cyclopentoxy)-4,6-dihydroxy-phenyl]-pyrrolidin-1-yl-methanone;-   (2-benzyloxy-4,6-dihydroxy-phenyl)-pyrrolidin-1-yl-methanone;-   (2-benzyloxy-4,6-dihydroxy-phenyl)-isoindolin-2-yl-methanone;-   (2-benzyloxy-4,6-dihydroxy-phenyl)-(1-piperidyl)methanone;-   (2-benzyloxy-4,6-dihydroxy-phenyl)-[(3S)-3-hydroxypyrrolidin-1-yl]methanone;-   (2-benzyloxy-4,6-dihydroxy-phenyl)-[(3R)-3-hydroxypyrrolidin-1-yl]methanone;-   (2-benzyloxy-4,6-dihydroxy-phenyl)-[(3R)-3-hydroxy-1-piperidyl]methanone;-   (2-benzyloxy-4,6-dihydroxy-phenyl)-[(3S)-3-hydroxy-1-piperidyl]methanone;-   (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-pyrrolidin-1-yl-methanone;-   (2-benzyloxy-3-ethyl-4,6-dihydroxy-phenyl)-pyrrolidin-1-yl-methanone;-   [2,4-dihydroxy-6-(2-pyridylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;-   [2,4-dihydroxy-6-[(1R)-1-phenylethoxy]phenyl]-pyrrolidin-1-yl-methanone;-   [2,4-dihydroxy-6-[(1R)-1-phenylethoxy]phenyl]-pyrrolidin-1-yl-methanone;-   [2-[(4-fluorophenyl)methoxy]-4,6-dihydroxy-phenyl]-pyrrolidin-1-yl-methanone;-   [2,4-dihydroxy-6-[(4-methoxyphenyl)methoxy]phenyl]-pyrrolidin-1-yl-methanone;-   [2,4-dihydroxy-6-(m-tolylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;-   (2-benzyloxy-4,6-dihydroxy-phenyl)-(5,7-dihydropyrrolo[3,4-b]pyridin-6-yl)methanone;-   (2-benzyloxy-4,6-dihydroxy-phenyl)-(4-methoxyisoindolin-2-yl)methanone;-   [2,4-dihydroxy-6-(pyrimidin-4-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;-   2,4-dihydroxy-6-(1H-pyrazol-3-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;-   [2,4-dihydroxy-6-(1H-triazol-4-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;-   (2-benzyloxy-4,6-dihydroxy-phenyl)-(5-bromoisoindolin-2-yl)methanone;-   methyl    2-(2-benzyloxy-4,6-dihydroxy-benzoyl)isoindoline-5-carboxylate;-   (2-benzyloxy-4,6-dihydroxy-phenyl)-(5-methoxyisoindolin-2-yl)methanone;-   (2-benzyloxy-4,6-dihydroxy-phenyl)-(5,6-dimethoxyisoindolin-2-yl)methanone;-   [2,4-dihydroxy-6-(1-phenylethoxy)phenyl]-isoindolin-2-yl-methanone;-   [2,4-dihydroxy-6-(1-phenylethoxy)phenyl]-(5-methoxyisoindolin-2-yl)methanone;-   [2,4-dihydroxy-6-(1-phenylethoxy)phenyl]-(5,6-dimethoxyisoindolin-2-yl)methanone;-   (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(5,7-dihydropyrrolo[3,4-b]pyridin-6-yl)methanone;-   5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[4,6-dihydroxy-3-methyl-2-(m-tolylmethoxy)phenyl]methanone;-   5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[2,4-dihydroxy-6-(m-tolylmethoxy)phenyl]methanone;-   5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]methanone;-   [4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-isoindolin-2-yl-methanone;-   5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[2,4-dihydroxy-6-(2-pyridylmethoxy)phenyl]methanone;-   (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-isoquinolin-2-yl)methanone;-   [2,4-dihydroxy-6-(2-pyridylmethoxy)phenyl]-isoindolin-2-yl-methanone;-   (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(4-bromoisoindolin-2-yl)methanone;-   (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-[4-(hydroxymethyl)isoindolin-2-yl]methanone;-   (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-[5-[(4-methylpiperazin-1-yl)methyl]isoindolin-2-yl]methanone;-   (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone;-   (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)methanone;-   (2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-2,6-naphthyridin-2-yl)methanone;-   3,4-dihydro-1H-isoquinolin-2-yl-[4,6-dihydroxy-3-methyl-2-(m-tolylmethoxy)phenyl]methanone;-   3,4-dihydro-1H-isoquinolin-2-yl-[4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]methanone;-   [4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone;-   [4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone;-   3,4-dihydro-1H-isoquinolin-2-yl-[2-[(4-fluorophenyl)methoxy]-4,6-dihydroxy-3-methyl-phenyl]methanone;-   (2-(benzyloxy)-4,6-dihydroxyphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;-   (4-aminoisoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone;-   (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-vinylisoindolin-2-yl)methanone;-   (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone;-   (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methanone;-   (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;-   (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone;-   (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methanone;-   (3,4-dihydroisoquinolin-2(1H)-yl)(4,6-dihydroxy-3-methyl-2-((1-methyl-1H-pyrazol-3-yl)methoxy)phenyl)methanone;-   (2-(benzyloxy)-4,6-dihydroxyphenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone;-   (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(isoindolin-2-yl)methanone;-   (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;-   (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;-   (S)-(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;-   (2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1-(hydroxymethyl)isoindolin-2-yl)methanone;-   (R)-(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5-((dimethylamino)methyl)isoindolin-2-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5-(morpholinomethyl)isoindolin-2-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(indolin-1-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxyphenyl)(indolin-1-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3,4-dihydroquinolin-1(2H)-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxyphenyl)(3,4-dihydroquinolin-1(2H)-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(morpholinomethyl)isoindolin-2-yl)methanone;-   2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;-   2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxamide;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(oxetan-3-ylamino)isoindolin-2-yl)methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(3-hydroxypiperidin-1-yl)isoindolin-2-yl)methanone;-   2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile;-   2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide;-   2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-methylisoindoline-5-carboxamide;-   2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide;-   2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-4-carboxamide;-   N-(2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)acetamide;-   ((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone;-   (4-(Azetidin-3-yl methoxy) isoindolin-2-yl) (2-(benzyloxy)    -4,6-dihydroxy -3-methylphenyl)-   methanone;-   (2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone;-   1-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)azetidine-3-carbonitrile;-   (4,6-Dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;-   (2-Ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;-   (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;-   (2-(Cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;    and-   (2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.

The various functional groups and substituents making up the compoundsof the Formula (I), or sub-formulae (I-I) to (I-XII), are typicallychosen such that the molecular weight of the compound of the formula (I)does not exceed 1000. More usually, the molecular weight of the compoundwill be less than 900, for example less than 800, or less than 750, orless than 700, or less than 650. More preferably, the molecular weightis less than 600 and, for example, is 550 or less.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic,formic, citric methane sulfonate or maleic acid. In addition, a suitablepharmaceutically acceptable salt of a compound of the invention which issufficiently acidic is an alkali metal salt, for example a sodium orpotassium salt, an alkaline earth metal salt, for example a calcium ormagnesium salt, an ammonium salt or a salt with an organic base whichaffords a pharmaceutically acceptable cation, for example a salt withmethylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001),for example by synthesis from optically active starting materials or byresolution of a racemic form. Some of the compounds of the invention mayhave geometric isomeric centres (E- and Z-isomers).

It is to be understood that the present invention encompasses alloptical, diastereoisomers and geometric isomers and mixtures thereofthat possess activity.

The present invention also encompasses compounds of the invention asdefined herein which comprise one or more isotopic substitutions. Forexample, H may be in any isotopic form, including 1H, 2H(D), and 3H (T);C may be in any isotopic form, including 12C, 13C, and 14C; and O may bein any isotopic form, including 16O and 18O; and the like.

It is also to be understood that certain compounds of the Formula (I),or sub-formulae (I-I) to (I-XII), may exist in solvated as well asunsolvated forms such as, for example, hydrated forms. It is to beunderstood that the invention encompasses all such solvated forms thatpossess activity.

It is also to be understood that certain compounds of the Formula (I),or sub-formulae (I-I) to (I-XII), may exhibit polymorphism, and that theinvention encompasses all such forms that possess activity.

Compounds of the Formula (I), or sub-formulae (I-I) to (I-XII), mayexist in a number of different tautomeric forms and references tocompounds of the Formula (I), or sub-formulae (I-I) to (I-XII), includeall such forms. For the avoidance of doubt, where a compound can existin one of several tautomeric forms, and only one is specificallydescribed or shown, all others are nevertheless embraced by Formula (I),or sub-formulae (I-I) to (I-XII). Examples of tautomeric forms includeketo-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, and nitro/aci-nitro.

Compounds of the Formula (I), or sub-formulae (I-I) to (I-XII),containing an amine function may also form N-oxides. A reference hereinto a compound of the Formula (I), or sub-formulae (I-I) to (I-XII), thatcontains an amine function also includes the N-oxide. Where a compoundcontains several amine functions, one or more than one nitrogen atom maybe oxidised to form an N-oxide. Particular examples of N-oxides are theN-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containingheterocycle. N-Oxides can be formed by treatment of the correspondingamine with an oxidizing agent such as hydrogen peroxide or a per-acid(e.g. a peroxycarboxylic acid), see for example Advanced OrganicChemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. Moreparticularly, N-oxides can be made by the procedure of L. W. Deady (Syn.Comm. 1977, 7, 509-514) in which the amine compound is reacted withm-chloroperoxybenzoic acid (mCPBA), for example, in an inert solventsuch as dichloromethane.

The compounds of Formula (I), or sub-formulae (I-I) to (I-XII), may beadministered in the form of a pro-drug which is broken down in the humanor animal body to release a compound of the invention. A pro-drug may beused to alter the physical properties and/or the pharmacokineticproperties of a compound of the invention. A pro-drug can be formed whenthe compound of the invention contains a suitable group or substituentto which a property-modifying group can be attached. Examples ofpro-drugs include in vivo cleavable ester derivatives that may be formedat a carboxy group or a hydroxy group in a compound of the Formula (I),or sub-formulae (I-I) to (I-XII), and in-vivo cleavable amidederivatives that may be formed at a carboxy group or an amino group in acompound of the Formula (I), or sub-formulae (I-I) to (I-XII).

Accordingly, the present invention includes those compounds of theFormula (I), or sub-formulae (I-I) to (I-XII), as defined hereinbefore,when made available by organic synthesis and when made available withinthe human or animal body by way of cleavage of a pro-drug thereof.Accordingly, the present invention includes those compounds of theFormula (I), or sub-formulae (I-I) to (I-XII), that are produced byorganic synthetic means and also such compounds that are produced in thehuman or animal body by way of metabolism of a precursor compound, thatis a compound of the Formula (I), or sub-formulae (I-I) to (I-XII), maybe a synthetically-produced compound or a metabolically-producedcompound.

A suitable pharmaceutically acceptable pro-drug of a compound of theFormula (I), or sub-formulae (I-I) to (I-XII), is one that is based onreasonable medical judgement as being suitable for administration to thehuman or animal body without undesirable pharmacological activities andwithout undue toxicity.

Various forms of pro-drug have been described, for example in thefollowing documents:—

a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, etal. (Academic Press, 1985);b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);c) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application ofPro-drugs”, by H. Bundgaard p. 113-191 (1991);

d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);

g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”,A.C.S. Symposium Series, Volume 14; and

h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, PergamonPress, 1987.

A suitable pharmaceutically acceptable pro-drug of a compound of theFormula (I), or sub-formulae (I-I) to (I-XII), that possesses a carboxygroup is, for example, an in vivo cleavable ester thereof. An in vivocleavable ester of a compound of the Formula I, or sub-formulae (I-I) to(I-XII), containing a carboxy group is, for example, a pharmaceuticallyacceptable ester which is cleaved in the human or animal body to producethe parent acid or parent alcohol. Suitable pharmaceutically acceptableesters for carboxy include (1-6C)alkyl esters such as methyl, ethyl andtert-butyl, (1-6C)alkoxymethyl esters such as methoxymethyl esters,(1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters,3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters suchas cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,2-oxo-1,3-dioxolenylmethyl esters such as5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and(1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such asmethoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

A suitable pharmaceutically acceptable pro-drug of a compound of theFormula (I), or sub-formulae (I-I) to (I-XII), that possesses a hydroxygroup is, for example, an in vivo cleavable ester or ether thereof. Anin vivo cleavable ester or ether of a compound of the Formula (I), orsub-formulae (I-I) to (I-XII), containing a hydroxy group is, forexample, a pharmaceutically acceptable ester or ether which is cleavedin the human or animal body to produce the parent hydroxy compound.Suitable pharmaceutically acceptable ester forming groups for a hydroxygroup include inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters). Further suitable pharmaceuticallyacceptable ester forming groups for a hydroxy group include(1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl andsubstituted benzoyl and phenylacetyl groups, (1-10C)alkoxycarbonylgroups such as ethoxycarbonyl, N,N-(1-6C)₂carbamoyl,2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ringsubstituents on the phenylacetyl and benzoyl groups include aminomethyl,N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl,piperazin-1-ylmethyl and 4-(1-4C)alkylpiperazin-1-ylmethyl. Suitablepharmaceutically acceptable ether forming groups for a hydroxy groupinclude α-acyloxyalkyl groups such as acetoxymethyl andpivaloyloxymethyl groups.

A suitable pharmaceutically acceptable pro-drug of a compound of theFormula (I), or sub-formulae (I-I) to (I-XII), that possesses a carboxygroup is, for example, an in vivo cleavable amide thereof, for examplean amide formed with an amine such as ammonia, a (1-4C)alkylamine suchas methylamine, a [(1-4C)alkyl]₂amine such as dimethylamine,N-ethyl-N-methylamine or diethylamine, a (1-4C)alkoxy-(2-4C)alkylaminesuch as 2-methoxyethylamine, a phenyl-(1-4C)alkylamine such asbenzylamine and amino acids such as glycine or an ester thereof.

A suitable pharmaceutically acceptable pro-drug of a compound of theFormula (I), or sub-formulae (I-I) to (I-XII), that possesses an aminogroup is, for example, an in vivo cleavable amide derivative thereof.Suitable pharmaceutically acceptable amides from an amino group include,for example an amide formed with (1-10C)alkanoyl groups such as anacetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetylgroups. Examples of ring substituents on the phenylacetyl and benzoylgroups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl,morpholinomethyl, piperazin-1-ylmethyl and4-(1-4C)alkyl)piperazin-1-ylmethyl.

The in vivo effects of a compound of the Formula (I), or sub-formulae(I-I) to (I-XII), may be exerted in part by one or more metabolites thatare formed within the human or animal body after administration of acompound of the Formula (I), or sub-formulae (I-I) to (I-XII). As statedhereinbefore, the in vivo effects of a compound of the Formula (I), orsub-formulae (I-I) to (I-XII), may also be exerted by way of metabolismof a precursor compound (a pro-drug).

Though the present invention may relate to any compound or particulargroup of compounds defined herein by way of optional, preferred orsuitable features or otherwise in terms of particular embodiments, thepresent invention may also relate to any compound or particular group ofcompounds that specifically excludes said optional, preferred orsuitable features or particular embodiments.

Suitably, the present invention excludes any individual compounds notpossessing the biological activity defined herein.

Synthesis

The compounds of the present invention can be prepared by any suitabletechnique known in the art. Particular processes for the preparation ofthese compounds are described further in the accompanying examples.

In the description of the synthetic methods described herein and in anyreferenced synthetic methods that are used to prepare the startingmaterials, it is to be understood that all proposed reaction conditions,including choice of solvent, reaction atmosphere, reaction temperature,duration of the experiment and workup procedures, can be selected by aperson skilled in the art.

It is understood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reaction conditions utilised.

It will be appreciated that during the synthesis of the compounds of theinvention in the processes defined herein, or during the synthesis ofcertain starting materials, it may be desirable to protect certainsubstituent groups to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how suchprotecting groups may be put in place, and later removed.

For examples of protecting groups see one of the many general texts onthe subject, for example, ‘Protective Groups in Organic Synthesis’ byTheodora Green (publisher: John Wiley & Sons). Protecting groups may beremoved by any convenient method described in the literature or known tothe skilled chemist as appropriate for the removal of the protectinggroup in question, such methods being chosen so as to effect removal ofthe protecting group with the minimum disturbance of groups elsewhere inthe molecule.

Thus, if reactants include, for example, groups such as amino, carboxyor hydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

By way of example, a suitable protecting group for an amino oralkylamino group is, for example, an acyl group, for example an alkanoylgroup such as acetyl, an alkoxycarbonyl group, for example amethoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, anarylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroylgroup, for example benzoyl. The deprotection conditions for the aboveprotecting groups necessarily vary with the choice of protecting group.Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonylgroup or an aroyl group may be removed by, for example, hydrolysis witha suitable base such as an alkali metal hydroxide, for example lithiumor sodium hydroxide. Alternatively an acyl group such as atert-butoxycarbonyl group may be removed, for example, by treatment witha suitable acid as hydrochloric, sulfuric or phosphoric acid ortrifluoroacetic acid and an arylmethoxycarbonyl group such as abenzyloxycarbonyl group may be removed, for example, by hydrogenationover a catalyst such as palladium-on-carbon, or by treatment with aLewis acid for example boron tris(trifluoroacetate). A suitablealternative protecting group for a primary amino group is, for example,a phthaloyl group which may be removed by treatment with an alkylamine,for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium, sodium hydroxide or ammonia. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

Resins may also be used as a protecting group.

The methodology employed to synthesise a compound of Formula (I), orsub-formulae (I-I) to (I-XII), will vary depending on the nature of R¹,R², R³, R⁴, R⁶ and R¹⁰ and any substituent groups or subgroupsassociated therewith. Suitable processes for their preparation aredescribed further in the accompanying Examples.

Once a compound of Formula (I), or sub-formulae (I-I) to (I-XII), hasbeen synthesised by any one of the processes defined herein, theprocesses may then further comprise the additional steps of:

(i) removing any protecting groups present;(ii) converting the compound Formula (I) into another compound ofFormula (I);(iii) forming a pharmaceutically acceptable salt, hydrate or solvatethereof; and/or(iv) forming a prodrug thereof.

An example of (ii) above is when a compound of Formula (I) issynthesised and then one or more of the groups R¹, R², R³, R⁴, R⁶ andR¹⁰ may be further reacted to change the nature of the group and providean alternative compound of Formula (I).

The resultant compounds of Formula (I), or sub-formulae (I-I) to(I-XII), can be isolated and purified using techniques well known in theart.

The compounds of Formula (I) may be synthesised by the synthetic routesshown in the Examples section below.

Biological Activity

The biological assays described in the Examples section herein may beused to measure the pharmacological effects of the compounds of thepresent invention.

Although the pharmacological properties of the compounds of Formula (I)vary with structural change, as expected, the compounds of the inventionwere found to be active in a PMS2 in vitro assay and in some cases alsoin a MLH1 in vitro assay described in the Examples section.

Pharmaceutical Compositions

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt, hydrateor solvate thereof, in association with a pharmaceutically acceptablediluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular,intraperitoneal or intramuscular dosing or as a suppository for rectaldosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

An effective amount of a compound of the present invention for use intherapy is an amount sufficient to treat or prevent a proliferativecondition referred to herein, slow its progression and/or reduce thesymptoms associated with the condition.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the individual treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well-known principles ofmedicine.

In using a compound of the invention for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.1 mg/kg to 75 mg/kg body weight is received, givenif required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous or intraperitoneal administration, a dose in the range, forexample, 0.1 mg/kg to 30 mg/kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.05 mg/kg to 25 mg/kg body weight will be used. Oraladministration may also be suitable, particularly in tablet form.Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of acompound of this invention.

Therapeutic Uses and Applications

The present invention provides compounds that function as inhibitors ofMLH1 and/or PMS2 activity (e.g. MLH1 activity or PMS2 activity or MLH1and PMS2 activity).

The compounds of Formula (I), or a pharmaceutically acceptable saltthereof, therefore have potential therapeutic uses in a variety ofdisease states in which the inhibition of MLH1 and/or PMS2 activity isbeneficial.

The present invention therefore provides a method of treating a diseaseor disorder in which the inhibition MLH1 and/or PMS2 activity (e.g. MLH1activity or PMS2 activity or MLH1 and PMS2 activity) is beneficial in apatient in need of such treatment, said method comprising administeringto said patient a therapeutically effective amount of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, or apharmaceutical composition as defined herein.

The present invention provides a method of inhibiting MLH1 and/or PMS2activity (e.g. MLH1 activity or PMS2 activity or MLH1 and PMS2activity), in vitro or in vivo, said method comprising contacting a cellwith an effective amount of a compound or a pharmaceutically acceptablesalt, hydrate or solvate thereof as defined herein.

The present invention provides a method of treating a proliferativedisorder in a patient in need of such treatment, said method comprisingadministering to said patient a therapeutically effective amount of acompound or a pharmaceutically acceptable salt, hydrate or solvatethereof as defined herein, or a pharmaceutical composition as definedherein.

The present invention provides a method of treating cancer in a patientin need of such treatment, said method comprising administering to saidpatient a therapeutically effective amount of a compound or apharmaceutically acceptable salt, hydrate or solvate thereof as definedherein, or a pharmaceutical composition as defined herein.

The present invention provides a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, or a pharmaceuticalcomposition as defined herein for use in therapy.

The present invention provides a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, or a pharmaceuticalcomposition as defined herein for use as a medicament.

The present invention provides a compound or a pharmaceuticallyacceptable salt, hydrate or solvate thereof as defined herein, or apharmaceutical composition as defined herein, for use in the treatmentof a proliferative disorder.

The present invention provides a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, or a pharmaceuticalcomposition as defined herein for use in the treatment of cancer. In aparticular embodiment, the cancer is human cancer. In a particularembodiment, the cancer is human cancer, in particular oestrogen positivecancers, such as breast cancer, or androgen receptor positive cancers,such as prostate cancer.

The present invention provides a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, as defined herein for usein the inhibition of MLH1 and/or PMS2 activity (e.g. MLH1 activity orPMS2 activity or MLH1 and PMS2 activity). Preferably, there is provideda compound, or a pharmaceutically acceptable salt, hydrate or solvatethereof, as defined herein, for use in the inhibition of PMS2 activity;most preferably, for use in the inhibition of PMS2 and MLH1 activity.

The present invention provides a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, as defined herein for usein the treatment of a disease or disorder in which the inhibition ofMLH1 and/or PMS2 activity (e.g. MLH1 activity or PMS2 activity or MLH1and PMS2 activity) is beneficial.

The present invention provides a use of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, as definedherein in the manufacture of a medicament for the treatment of aproliferative disorder.

The present invention provides a use of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, as definedherein in the manufacture of a medicament for the treatment of cancer.

The present invention provides a use of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, as definedherein in the manufacture of a medicament for the inhibition of MLH1and/or PMS2 activity (e.g. MLH1 activity or PMS2 activity or MLH1 andPMS2 activity).

The present invention provides a use of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, as definedherein in the manufacture of a medicament for the treatment of a diseaseor disorder in which the inhibition of MLH1 and/or PMS2 activity (e.g.MLH1 activity or PMS2 activity or MLH1 and PMS2 activity) is beneficial.

The term “proliferative disorder”, “proliferative condition” and“proliferative disease” are used interchangeably herein and pertain toan unwanted or uncontrolled cellular proliferation of excessive orabnormal cells which is undesired, such as, neoplastic or hyperplasticgrowth, whether in vitro or in vivo.

In the above-outlined aspects of the invention, the proliferativedisorder is suitably cancer, and the cancer is suitably a human cancer.In particular, the compounds of the present invention will be useful forthe treatment of any cancer in which a mis-match repair inhibition isbeneficial. Any suitable cancer may be targeted (e.g. adenoid cysticcarcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendixcancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann Syndrome,bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dube Syndrome, bladdercancer, bone cancer, brain stem glioma, brain tumor, breast cancer,Carney Complex, central nervous system tumors, cervical cancer,colorectal cancer, Cowden Syndrome, craniopharyngioma, desmoplasticinfantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma,eye cancer, eyelid cancer, familial adenomatous polyposis, familialGIST, familial malignant melanoma, familial non-VHL clear cell renalcell carcinoma, familial pancreatic cancer, gallbladder cancer,gastrointestinal stromal tumor—GIST, germ cell tumor, gestationaltrophoblastic disease, head and neck cancer, hereditary breast andovarian cancer, hereditary diffuse gastric cancer, hereditaryleiomyomatosis and renal cell cancer, hereditary mixed polyposissyndrome, hereditary pancreatitis, hereditary papillary renal carcinoma,juvenile polyposis syndrome, kidney cancer, lacrimal gland tumor,laryngeal and hypopharyngeal cancer, leukemia (acute lymphoblasticleukamia (ALL), acute myeloid leukemia (AML), B-cell prolymphocyticleukemia, hairy cell leukemia, chronic lymphocytic leukemia (CLL),chronic myeloid leukemia (CML), chronic T-cell lymphocytic leukemia,eosinophilic leukemia), Li-Fraumeni Syndrome, liver cancer, lung cancer(non-small cell lung cancer, small cell lung cancer), Lymphoma (Hodgkin,non-Hodgkin), Lynch Syndrome, mastocytosis, medulloblastoma, melanoma,meningioma, mesothelioma, multiple endocrine neoplasia Type 1 & 2,multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplasticsyndromes (MDS), nasal cavity and paranasal sinus Cancer, nasopharyngealCancer, neuroblastoma, neuroendocrine tumors (e.g. of thegastrointestinal tract, lung or pancreas), neurofibromatosis Type 1 & 2,nevoid basal cell carcinoma syndrome, oral and oropharyngeal cancer,osteosarcoma, ovarian/fallopian tube/peritoneal cancer, pancreaticcancer, parathyroid cancer, penile cancer, Peutz-Jeghers Syndrome,pheochromocytoma, paraganglioma, pituitary gland tumor, pleuropulmonaryblastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivarygland cancer, sarcoma (e.g. Kaposi or soft tissue), skin cancer, smallbowel cancer, stomach cancer, testicular cancer, thymoma and thymiccarcinoma, thyroid cancer, tuberous sclerosis complex, uterine cancer,vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Waldenstrom'smacroglobulinemia, Werner syndrome, Wilms Tumor and xerodermapigmentosum). Particular cancers of interest include haematologicalcancers such as lymphomas (including diffuse large B-cell lymphoma(DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL) andangioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acutelymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)),multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC),colorectal cancer, endometrial cancer, gastro-oesophageal cancer,neuroendocrine cancers, osteosarcomas, prostate cancer, pancreaticcancer, small intestine cancer, bladder cancer, rectal cancer,cholangiocarcinoma, CNS cancer, thyroid cancer, head and neck cancer,oesophageal cancer, and ovarian cancer.

The compounds of the present invention may also be used to treat tripletdiseases.

Thus, a further aspect of the present invention provides a method oftreating a triplet disorder (e.g. Huntington's disease (HD), myotonicdystrophy type 1 (DM1), fragile X syndrome type A (FRAXA), Friedreich'sataxia (FRDA), and spinocerebellar ataxias (SCAs)) in a patient in needof such treatment, said method comprising administering to said patienta therapeutically effective amount of a compound or a pharmaceuticallyacceptable salt, hydrate or solvate thereof as defined herein, or apharmaceutical composition as defined herein.

According to a further aspect of the present invention, there isprovided a compound, or a pharmaceutically acceptable salt, hydrate orsolvate thereof, or a pharmaceutical composition as defined herein foruse in the treatment of a triplet disorder. In a particular embodiment,the triplet disorder is selected from the group consisting ofHuntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile Xsyndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellarataxias (SCAs).

According to a further aspect of the present invention, there isprovided the use of a compound, or a pharmaceutically acceptable salt,hydrate or solvate thereof, as defined herein in the manufacture of amedicament for the treatment of a triplet disorder. In a particularembodiment, the triplet disorder is selected from the group consistingof Huntington's disease (HD), myotonic dystrophy type 1 (DM1), fragile Xsyndrome type A (FRAXA), Friedreich's ataxia (FRDA), and spinocerebellarataxias (SCAs).

Routes of Administration

The compounds of the invention or pharmaceutical compositions comprisingthese compounds may be administered to a subject by any convenient routeof administration, whether systemically, peripherally or topically(i.e., at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g, byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including intratumoral, subcutaneous,intradermal, intramuscular, intravenous, intra-arterial, intracardiac,intrathecal, intraspinal, intracapsular, subcapsular, intraorbital,intraperitoneal, intratracheal, subcuticular, intraarticular,subarachnoid, and intrasternal; by implant of a depot or reservoir, forexample, subcutaneously or intramuscularly.

Combination Therapies

The compounds of the present invention may be administered as a soletherapy or may involve, in addition to a compound of the invention,conventional surgery or radiotherapy or chemotherapy or a targetedagent. Such chemotherapy or targeted agent may include one or more ofthe following categories:

-   (i) Antiproliferative/antineoplastic drugs and combinations thereof,    as used in medical oncology, such as, but not limited to, alkylating    agents (for example cis-platin, oxaliplatin, carboplatin,    cyclophosphamide, nitrogen mustard, melphalan, chlorambucil,    busulphan, temozolamide and nitrosoureas); antimetabolites (for    example gemcitabine and antifolates such as fluoropyrimidines like    5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine    arabinoside, and hydroxyurea); antitumour antibiotics (for example    anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,    epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);    antimitotic agents (for example vinca alkaloids like vincristine,    vinblastine, vindesine and vinorelbine and taxoids like taxol and    taxotere and polokinase inhibitors); and topoisomerase inhibitors    (for example epipodophyllotoxins like etoposide and teniposide,    amsacrine, topotecan and camptothecin);-   (ii) cytostatic agents such as, but not limited to, antioestrogens    (for example tamoxifen, fulvestrant, toremifene, raloxifene,    droloxifene and iodoxyfene), antiandrogens (for example    bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH    antagonists or LHRH agonists (for example goserelin, leuprorelin and    buserelin), steroid hormones, including progestogens (for example    megestrol acetate) and corticosteroids (for example dexamethasone,    prednisone and prednisolone), aromatase inhibitors (for example as    anastrozole, letrozole, vorazole and exemestane) and inhibitors of    5α-reductase such as finasteride;-   (iii) anti-invasion agents such as, but not limited to, c-Src kinase    family inhibitors    4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline    (AZD0530; International Patent Application WO 01/94341),    N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide    (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661),    bosutinib (SKI-606), and metalloproteinase inhibitors such as    marimastat, inhibitors of urokinase plasminogen activator receptor    function or antibodies to Heparanase;-   (iv) inhibitors of growth factor function such as, but not limited    to, growth factor antibodies and growth factor receptor antibodies    (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the    anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab    [Erbitux, C225] and any growth factor or growth factor receptor    antibodies disclosed by Stern et al. (Critical reviews in    oncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors also    include tyrosine kinase inhibitors, for example inhibitors of the    epidermal growth factor family (for example EGFR family tyrosine    kinase inhibitors such as    N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine    (gefitinib, ZD1839),    N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine    (erlotinib, OSI-774) and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine    (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);    inhibitors of the hepatocyte growth factor family; inhibitors of the    insulin growth factor family; inhibitors of the platelet-derived    growth factor family such as imatinib and/or nilotinib (AMN107);    inhibitors of serine/threonine kinases (for example Ras/Raf    signalling inhibitors such as farnesyl transferase inhibitors, for    example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib    (SCH66336)), inhibitors of cell signalling through MEK and/or AKT    kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase    inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF    receptor (insulin-like growth factor) kinase inhibitors; aurora    kinase inhibitors and cyclin dependent kinase inhibitors such as    CDK2 and/or CDK4 inhibitors;-   (v) antiangiogenic agents such as, but not limited to, those which    inhibit the effects of vascular endothelial growth factor, [for    example the anti-vascular endothelial cell growth factor antibody    bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine    kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787),    sunitinib (SU11248), axitinib (AG-013736) and pazopanib (GW 786034).-   (vi) vascular damaging agents such as, but not limited to,    Combretastatin A4 and compounds disclosed in International Patent    Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO    02/04434 and WO 02/08213;-   (vii) an endothelin receptor antagonist, for example zibotentan    (ZD4054) or atrasentan;-   (viii) antisense therapies, such as, but not limited to, those    directed to targets listed above, such as ISIS 2503, an anti-ras    antisense;-   (ix) immunotherapy approaches, including for example cancer    vaccines, antibody, viral (oncolytic viruses) and small molecule or    cell therapy approaches to increase the immunogenicity of patient    tumour cells and/or facilitate a cell mediated anti-tumour response.    Such therapies could include, but are not limited to, OX40 agonists,    cGAS-STING agonists, ENPP1 inhibitors, CD38 inhibitors, TBK1    inhibitors, A2a receptor antagonists, PI3 kinase inhibitors, TLR7/8    agonists, IDO inhibitors, Arginase inhibitors, BTK inhibitors and    Bromodomain inhibitors; transduction with microbial vectors of    cancer antigens, direct transduction of cancer antigens into antigen    presenting cells, treatment with immune cells specific for cancer    antigens (e.g. CAR-T), treatment with antibodies, antibody fragments    and antibody drug conjugates that enable the immune system to    recognise tumour cells.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

According to this aspect of the invention there is provided acombination for use in the treatment of a cancer (for example a cancerinvolving a solid tumour) comprising a compound of the invention asdefined hereinbefore, or a pharmaceutically acceptable salt or solvatethereof, and an anti-tumour agent.

According to this aspect of the invention there is provided acombination for use in the treatment of a proliferative condition, suchas cancer (for example a cancer involving a solid tumour), comprising acompound of the invention as defined hereinbefore, or a pharmaceuticallyacceptable salt or solvate thereof, and any one of the anti-tumouragents listed herein above.

In a further aspect of the invention there is provided a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof, foruse in the treatment of cancer in combination with another anti-tumouragent, optionally selected from one listed herein above.

In a further aspect of the invention there is provided a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof, foruse in the treatment of cancer in combination with a tyrosine kinaseinhibitor, optionally selected from one listed herein above.

Herein, where the term “combination” is used it is to be understood thatthis refers to simultaneous, separate or sequential administration. Inone aspect of the invention “combination” refers to simultaneousadministration. In another aspect of the invention “combination” refersto separate administration. In a further aspect of the invention“combination” refers to sequential administration. Where theadministration is sequential or separate, the delay in administering thesecond component should not be such as to lose the beneficial effect ofthe combination.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the invention,or a pharmaceutically acceptable salt or solvate thereof, in combinationwith an anti-tumour agent (optionally selected from one listed hereinabove), in association with a pharmaceutically acceptable diluent orcarrier.

Combination Therapy with Immune Modulating Treatments

Immune Checkpoint Inhibitors

Immune checkpoint proteins present on immune cells and/or cancer cells[e.g. CTLA4 (also known as cytotoxic T-lymphocyte-associated protein 4and CD152), LAG3 (also known as lymphocyte-activation gene 3 and CD223),PD1 (also known as programmed cell death protein 1 and CD279), PD-L1(also known as programmed death-ligand 1 and CD274), TIM-3 (also knownas T-cell immunoglobulin mucin-3) and TIGIT (also known as T-cellImmunoreceptor with Ig and ITIM domains) are molecular targets that havebeen found to play an important role in regulating anti-tumour immuneresponses. Inhibitors of these immune checkpoint proteins (e.g. CTLA4,LAG3, PD1, PD-L1, TIM-3 and/or TIGIT inhibitors) promote an anti-tumourimmune response that can be utilised to effectively treat certain formsof cancer.

Immune Stimulators

Monoclonal antibodies, bispecific antibodies, recombinant ligands andsmall molecule therapeutics that bind to stimulatory receptors on immunecells can facilitate an effective anti-tumour response. Such receptorsmay be involved in cell-to-cell contact for example contact betweentumour cell and immune cell or between two types of immune cells, otherreceptors may bind to soluble factors that stimulate an immune response.In one such embodiment antibodies, bispecifics, recombinant proteins orsmall molecule therapeutics can activate stimulatory receptors,including, but not limited to, 4-1BB, OX40, cGAS-STING, CD27, CD40, andDR3 that enhance anti-tumour immunity.

Modulators of antigen processing may facilitate the presentation ofneoantigenic peptides on the cell surface to enhance an effectiveanti-tumour response. In one such embodiment inhibitors of theendoplasmic reticulum aminopeptidases ERAP1 and ERAP2 may stimulateanti-tumour immunity.

In one aspect, the present invention relates to a combination comprisinga compound as defined herein, or a pharmaceutically acceptable saltthereof, and an immune checkpoint inhibitor or immune stimulator asdefined herein, or a pharmaceutically acceptable salt thereof, for usein the treatment of a proliferative disorder.

In another aspect, the present invention relates to a use of acombination comprising a compound as defined herein, or apharmaceutically acceptable salt thereof, and an immune checkpointinhibitor or immune stimulator as defined herein, or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for treatingof a proliferative disorder.

In another aspect, the present invention relates to a method of treatingof a proliferative disorder in a subject in need thereof comprisingadministering to said subject a combination comprising a compound asdefined herein, or a pharmaceutically acceptable salt thereof, and animmune checkpoint inhibitor or immune stimulator as defined herein, or apharmaceutically acceptable salt thereof, as defined herein.

In another aspect, the present invention relates to a compound asdefined herein, or a pharmaceutically acceptable salt thereof, asdefined herein for use in the treatment of a proliferative disorder,wherein the compound, or a pharmaceutically acceptable salt thereof, isfor simultaneous, separate or sequential administration with an immunecheckpoint inhibitor, or immune stimulator, or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention relates to an immune checkpointinhibitor or immune stimulator, or a pharmaceutically acceptable saltthereof, for use in the treatment of a proliferative disorder, whereinthe immune checkpoint inhibitor is for simultaneous, separate orsequential administration with a compound as defined herein, or apharmaceutically acceptable salt thereof, as defined herein.

In another aspect, the present invention relates to a use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, asdefined herein in the manufacture of a medicament for treating aproliferative disorder, wherein the medicament is for simultaneous,separate or sequential administration with an immune checkpointinhibitor or immune stimulator, or a pharmaceutically acceptable saltthereof.

In another aspect, the present invention relates to a use of an immunecheckpoint inhibitor or immune stimulator, or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for treatinga proliferative disorder, wherein the medicament is for simultaneous,separate or sequential administration with a compound as defined herein,or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a method of treatinga proliferative disorder comprising administering to a subject in needthereof a therapeutically effective amount of a compound as definedherein, or a pharmaceutically acceptable salt thereof, as defined hereinand an immune checkpoint inhibitor or immune stimulator as definedherein, or a pharmaceutically acceptable salt thereof, eithersequentially, separately or simultaneously

Any immune checkpoint inhibitor or immune stimulator may be used in thecombination therapy defined herein.

In one embodiment, the immune stimulator is selected from a 4-1BBstimulator, a OX40 stimulator, a CD27 stimulator, a CD40 stimulator, anda DR3 stimulator. In another embodiment the immune checkpoint inhibitoris selected from a PD1-inhibitor, a PD-L1 inhibitor, a LAG3 inhibitor,CTLA-4 inhibitor, a TIM-3 inhibitor and/or a TIGIT inhibitor. In aparticular embodiment, the immune checkpoint inhibitor is a PD1 or PD-L1inhibitor.

PD-1 is a cell surface receptor protein present on immune cells such asT cells. PD-1 plays an important role in down-regulating the immunesystem and promoting self-tolerance by suppressing T cell activation.The PD-1 protein is an immune checkpoint that guards againstautoimmunity through a dual mechanism of promoting apoptosis (programmedcell death) in antigen specific T cells in lymph nodes, whilesimultaneously reducing apoptosis in regulatory T cells(anti-inflammatory suppressive T cells).

PD-1 therefore inhibits the immune system. This prevents autoimmunediseases, but it can also prevent the immune system from killing cancercells.

PD1 binds two ligands, PD-L1 and PD-L2. PD-L1 is of particular interestas it is highly expressed in several cancers and hence the role of PD1in cancer immune evasion is well established. Monoclonal antibodiestargeting PD-1 that boost the immune system are approved or are beingdeveloped for the treatment of cancer. Many tumour cells express PD-L1,an immunosuppressive PD-1 ligand; inhibition of the interaction betweenPD-1 and PD-L1 can enhance T-cell responses in vitro and mediatepreclinical antitumour activity. This is known as immune checkpointblockade.

Examples of drugs that target PD-1 include pembrolizumab (Keytruda) andnivolumab (Opdivo). These drugs have been shown to be effective intreating several types of cancer, including melanoma of the skin,non-small cell lung cancer, kidney cancer, bladder cancer, head and neckcancers, and Hodgkin lymphoma. They are also being studied for useagainst many other types of cancer. Examples of drugs in developmentinclude BMS-936559 (Bristol Myers Squibb), MGA012 (MacroGenics) andMEDI-0680 (MedImmune).

Examples of drugs that inhibit PD-L1 include atezolizumab (Tecentriq),avelumab (Bavencio) and durvalumab (Imfinzi). These drugs have also beenshown to be helpful in treating different types of cancer, includingbladder cancer, non-small cell lung cancer, and Merkel cell skin cancer(Merkel cell carcinoma). They are also being studied for use againstother types of cancer.

Examples of LAG3 inhibitors include BMS-986016/Relatlimab, TSR-033,REGN3767, MGDO13 (bispecific DART binding PD-1 and LAG-3), GSK2831781and LAG525.

Examples of CTLA-4 inhibitors include MDX-010/lpilimumab, AGEN1884, andCP-675,206/Tremelimumab.

Examples of TIM-3 inhibitors include MBG453 (Novartis), TSR-022(Tesaro), and LY3321367 (Lilly).

Examples of TIGIT inhibitors include Tiragolumab (MTIG7192A; RG6058;Genentech/Roche), AB154 (Arcus Bioscience), MK-7684 (Merck), BMS-986207(Bristol-Myers Squibb), ASP8374 (Astellas Pharma; Potenza Therapeutics).

In one embodiment, the immune checkpoint inhibitor is selected fromBMS-986016/Relatlimab, TSR-033, REGN3767, MGDO13 (bispecific DARTbinding PD-1 and LAG-3), GSK2831781, LAG525, MDX-010/Ipilimumab,AGEN1884, and CP-675,206/Tremelimumab, pembrolizumab, nivolumab,atezolizumab, avelumab, durvalumab, MBG453, TSR-022, LY3321367,Tiragolumab (MTIG7192A; RG6058), AB154, MK-7684, BMS-986207, and/orASP8374 or a pharmaceutically acceptable salt or solvate thereof.

Combination Therapy with DNA Damage Response Modulators

The compounds of the present invention are particularly suited to use incombination with agents that act as DNA damage response modulators, e.g.PARP inhibitors, ATM inhibitors and ATR inhibitors.

In one aspect, the present invention relates to a combination comprisinga compound as defined herein, or a pharmaceutically acceptable saltthereof, and a DNA damage response modulator (e.g. a PARP inhibitor, anATM inhibitor and/or an ATR inhibitor), or a pharmaceutically acceptablesalt thereof, for use in the treatment of a proliferative disorder.

In another aspect, the present invention relates to a use of acombination comprising a compound as defined herein, or apharmaceutically acceptable salt thereof, and a DNA damage responsemodulator (e.g. a PARP inhibitor, an ATM inhibitor and/or an ATRinhibitor), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for treating of a proliferative disorder.

In another aspect, the present invention relates to a method of treatingof a proliferative disorder in a subject in need thereof comprisingadministering to said subject a combination comprising a compound asdefined herein, or a pharmaceutically acceptable salt thereof, and a DNAdamage response modulator (e.g. a PARP inhibitor, an ATM inhibitorand/or an ATR inhibitor), or a pharmaceutically acceptable salt thereof,as defined herein.

In another aspect, the present invention relates to a compound asdefined herein, or a pharmaceutically acceptable salt thereof, asdefined herein for use in the treatment of a proliferative disorder,wherein the compound, or a pharmaceutically acceptable salt thereof, isfor simultaneous, separate or sequential administration with a DNAdamage response modulator (e.g. a PARP inhibitor, an ATM inhibitorand/or an ATR inhibitor), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, asdefined herein in the manufacture of a medicament for treating aproliferative disorder, wherein the medicament is for simultaneous,separate or sequential administration with a DNA damage responsemodulator (e.g. a PARP inhibitor, an ATM inhibitor and/or an ATRinhibitor), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a method of treatinga proliferative disorder comprising administering to a subject in needthereof a therapeutically effective amount of a compound as definedherein, or a pharmaceutically acceptable salt thereof, as defined hereinand a DNA damage response modulator (e.g. a PARP inhibitor, an ATMinhibitor and/or an ATR inhibitor), or a pharmaceutically acceptablesalt thereof, either sequentially, separately or simultaneously

Any DNA damage response modulator (e.g. a PARP inhibitor, an ATMinhibitor and/or an ATR inhibitor) may be used in the combinationtherapy defined herein.

Probe Compounds

The present invention further relates to novel probe molecules formed bylinking a compound of the present invention as defined herein to adetection moiety via a linker group. The present invention also relatesto methods of synthesising these novel probe molecules and to their usein assays and screens for determining the binding of a test molecule tothe ATP-binding site of a target protein, such as, for example, theMismatch Repair (MMR) component proteins PMS2 and MLH1, or fordetermining the location and/or quantity of such target proteins in abiological sample.

In one aspect, the present invention provides a probe compoundcomprising compound of the Formula (I), or sub-formulae (I-I) to(I-XII), or a salt thereof, bound to a detection moiety by a linker.

In another aspect, the present invention provides a method ofsynthesising a probe compound, or a salt thereof, as defined herein.

In another aspect, the present invention provides the use of a probecompound, or a salt thereof, as defined herein in a displacement assayto determine the binding affinity of a test molecule to the ATP-bindingsite of a target protein. In an embodiment, the target protein isselected from MLH1, PMS2 or HSP90. In a particular embodiment, thetarget protein is MLH1 or PMS2.

In another aspect, the present invention provides a probe compound, or asalt thereof, for use in a displacement assay to determine the bindingaffinity of a test molecule for the ATP-binding site of a targetprotein. In an embodiment, the target protein is selected from MLH1,PMS2 or HSP90. In a particular embodiment, the target protein is MLH1 orPMS2.

In another aspect, the present invention provides an assay fordetermining the binding affinity of a test molecule for the ATP-bindingsite of a target protein, the assay comprising:

(i) incubating a test molecule with the target protein in the presenceof a probe compound, or a salt thereof, as defined herein; and(ii) determining whether a probe compound is displaced from theATP-binding site of the target protein.In an embodiment, the target protein is selected from MLH1, PMS2 orHSP90. In a particular embodiment, the target protein is MLH1 or PMS2.

In another aspect, the present invention provides a method fordetermining the binding affinity of a test molecule for the ATP-bindingsite of a target protein, the assay comprising:

-   -   (i) incubating a test molecule with the target protein in the        presence of a probe compound, or a salt thereof, as defined        herein; and    -   (ii) determining whether a probe compound is displaced from the        ATP-binding site of the target protein.

In another aspect, the present invention provides an assay fordetermining the location and/or quantity of a target protein presentwithin a biological sample, the assay comprising:

-   -   (i) contacting the biological sample with a probe compound, or a        salt thereof, as defined herein; and    -   (ii) determining location and/or quantity of the compound        present within the sample by detecting the location and/or        intensity of the detection moieties of the compounds of formula        I present within the biological sample.

Suitably, the present invention relates to a probe compound of formulaB, or a salt thereof:

wherein:R¹, R², R³, R⁴, and R⁶ are each as defined herein;R¹⁰ is a group R¹⁰ as defined herein connected to L;L is a linker; andQ is a detection moiety.

The linker group L may be any suitable linker moiety that connects thedetection moiety Q to the remainder of the probe compound of formula B.

Suitably, the linker group L is 3 to 30 atoms in length, more suitably,4 to 20 atoms in length and even more suitably 5 to 18 atoms in length.In a particular group of probe compounds of formula I or II definedherein, L is 5 to 12 atoms in length.

The detection moiety Q can be any moiety that can enable the probecompound of formula I to be detected and quantified. As describedfurther below, the probe compounds of formula I defined herein aredesigned to be used in displacement assays, whereby the ability of atest compound to displace the probe compound of formula I from theATP-binding site of target protein (e.g. MLH1 or PMS2) can be used todetermine the binding affinity of that test compound for the ATP-bindingsite of the target protein. Thus, the detection moiety Q can be anymoiety that can be readily detected and quantified. In certaincircumstances, the detection moiety Q enables any probe compounds offormula I that have been displaced (i.e. is “unbound”) from theATP-binding site of the target protein to be detected and quantified. Incertain embodiments of the invention, this may be achieved by collectingany displaced or “unbound” compound of formula I from the test sampleand assaying the sample to determine how much unbound probe compound ispresent. This will in turn give an indication of how much of the probecompound present in the sample has been displaced by the test compound.

It will therefore be appreciated that the nature of detection moiety Qis not critical as long as it can be used to enable the amount of theprobe compound of formula I present in a sample to be determined. Aperson skilled in the art will be able to select a suitable detectionmoiety Q and a suitable methodology for detecting and quantifying theamount of the compound of formula I in a sample, in particular to detectthe amount of the probe compound of formula I that has been displacedfrom the ATP binding site of a target protein by a test compound.

Suitably, the detection moiety Q is selected from the group consistingof a fluorophore, an oligonucleotide, a biomolecule, a molecular sensor,a protein, or a peptide.

In embodiments where the detection moiety Q is an oligonucleotide, abiomolecule, a molecular sensor, a protein, or a peptide, then anysuitable technique known in the art for detecting and quantifying theamount of the oligonucleotide, biomolecule, molecular sensor, protein,or peptide present may be utilised. For example, a fluorescentlylabelled secondary probe may be used that is capable of specificallybinding to the detection moiety Q of the probe compound of formula Iand, once any excess of the secondary probe has been removed, the amountof binding of the secondary probe to detection moiety Q of the compoundfor formula I can be detected and quantified, thereby enabling theamount of the probe compound of formula I to be determined.

For example, if Q is an oligonucleotide, then a secondary probe having asuitable detectable label, e.g. a fluorophore or radio-label, and acomplimentary oligonucleotide sequence capable of hybridising to Q canbe used to detect and quantify the amount of the probe compound offormula I present in sample (and suitably the amount of the probecompound displaced from the ATP-binding site of the target protein by atest compound). Similarly, if Q is a protein or peptide, then asecondary probe may be an antibody capable of selectively binding tothat protein or peptide and a suitable detectable label, e.g. afluorophore or radio-label.

More suitably, the detection moiety Q is a fluorophore. In such cases,the compound for formula I can be used in a fluorescence polarisationassay. In a particular group of probe compounds of formula I, thedetection moiety Q is a fluorophore selected from the group consistingof AlexaFluor dyes, Cyanine dyes, fluorescein, BODIPY or BODIPYderivatives (e.g. BODIPY TMR), TAMRA, Oregon Green dyes, FITC, Ru(bpy)3,Rhodamine dyes, Acridine orange, and Texas Red. In a further group ofprobe compounds of formula I, the detection moiety Q is a fluorophoreselected from the group consisting of AlexaFluor-647, AlexaFluor-633,AlexaFluor-594, AlexaFluor-488, Cyanine-5B, Cyanine-3B, Fluorescein,BODIPY TMR, TAMRA, Oregon Green 488, Oregon Green 514, FITC, Ru(bpy)3,Rhodamine dyes, Acridine orange, and Texas Red.

A suitable salt of a probe compound of the invention is, for example, anacid-addition salt of a compound of the invention which is sufficientlybasic, for example, an acid-addition salt with, for example, aninorganic or organic acid, for example hydrochloric, hydrobromic,sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonateor maleic acid. In addition, a suitable salt of a compound of theinvention which is sufficiently acidic is an alkali metal salt, forexample a sodium or potassium salt, an alkaline earth metal salt, forexample a calcium or magnesium salt, an ammonium salt or a salt with anorganic base.

The present invention also encompasses probe compounds of the inventionas defined herein which comprise one or more isotopic substitutions. Forexample, H may be in any isotopic form, including ¹H, ²H (D) and ³H (T);C may be in any isotopic form, including ¹²C, ¹³C and ¹⁴C; and O may bein any isotopic form, including ¹⁶O and ¹⁸O; and the like.

It is also to be understood that certain probe compounds of the formula(I) may exist in solvated as well as unsolvated forms such as, forexample, hydrated forms.

It is also to be understood that certain probe compounds of the formula(I) may exhibit polymorphism, and that the invention encompasses allsuch polymorphic forms.

Certain probe compounds of formula (I) may also exist in a number ofdifferent tautomeric forms and references to compounds of the formula(I) include all such forms.

Synthesis of the Probe Compounds

In another aspect, the present invention provides a method ofsynthesising a probe compound of formula B, or a salt thereof, asdefined herein.

The probe compounds of the present invention can be prepared by anysuitable technique known in the art.

EXAMPLES

While specific embodiments of the invention have been described hereinfor the purpose of reference and illustration, various modificationswill be apparent to a person skilled in the art without departing fromthe scope of the invention as defined by the appended claims. Referenceis made to the accompanying figures, in which:

FIG. 1 shows the reaction scheme for2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile(Example 82);

FIG. 2 shows the reaction scheme for2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide(Example 83);

FIG. 3 shows the reaction scheme for2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide(Example 85);

FIG. 4 shows the reaction scheme for((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone(Example 88);

FIG. 5 shows the reaction scheme for (4-(Azetidin-3-yl methoxy)isoindolin-2-yl) (2-(benzyloxy) -4,6-dihydroxy-3-methylphenyl)methanone(Example 89);

FIG. 6 shows the reaction scheme for(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone(Example 90);

FIG. 7 shows the reaction scheme for(4,6-Dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone(Example 92);

FIG. 8 shows the reaction scheme for(2-Ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone(Example 93);

FIG. 9 shows the reaction scheme for(2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone(Example 94);

FIG. 10 shows the reaction scheme for(2-(Cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone(Example 95);

FIG. 11 shows the reaction scheme for(2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Example 96);

FIG. 12 shows the reaction scheme for4-formyl-5-(prop-2-yn-1-yloxy)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 37);

FIG. 13 shows the reaction scheme forN,N-Dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)methanamine(Intermediate 42);

FIG. 14 shows the reaction scheme forN,N-Dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)methanamine(Intermediate 43);

FIG. 15 shows the reaction scheme for1-(isoindolin-5-yl)-N,N-dimethylmethanamine hydrochloride (Intermediate46); and

FIG. 16 shows the reaction scheme for 4-((4-Methylpiperazin-1-yl)methyl)isoindoline hydrochloride (Intermediate 48).

ABBREVIATIONS

Boc for tert-butyloxycarbonylDAST for diethylaminosulfur trifluorideDBU for 1,8-diazabicyclo(5.4.0)undec-7-eneDCC for dicyclohexylcarbodiimideDCE for 1,1-dichloroethaneDCM for dichloromethaneDEA for diethanolamineDEAD for diethyl azodicarboxylateDIAD for diisopropyl azodicarboxylateDIBAL for Diisobutylaluminium hydrideDIPEA for N,N-diisopropylethylamine, Hünig's base

DMA for N,N-dimethylacetamide

DMAP for 4-(dimethylamino) pyridine

DMF for N,N-dimethylformamide

DMSO for dimethylsulfoxide.EDC for 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimideEtOAc for ethyl acetateh for hoursHATU forN-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxideHBTU for(1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylmethaniminiumhexafluorophosphate

HOBT for N-hydroxybenzotriazole HPLC for High Pressure LiquidChromatography.

LAH for lithium aluminium hydrideIPA for isopropyl alcohol

LCMS for Liquid Chromatography-Mass Spectrometry

LDA for Lithium diisopropylamideLiHMDS for Lithium bis(trimethylsilyl)amidemCPBA for meta-chloroperoxybenzoic acid

MI for Molecular Ion

Min for minutesMgSO₄ anhydrous magnesium sulfateMW for microwave

NBS for N-bromosuccinamide NCS for N-chlorosuccinamide

NFOBS for N-fluoro-o-benzenedisulfonimide

NFSI for N-fluorobenzenesulfonimide NHS for N-hydroxysuccinimide NIS forN-iodosuccinamide NMM for N-methylmorpholine

NMP for 1-methyl-2-pyrrolidinone

NMR for Nuclear Magnetic Resonance.

PdCl₂(PPh₃)₂ for Bis(triphenylphosphine)palladium chloridePd(dppf)₂Cl₂ for[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(dppf)₂Cl₂·DCM for[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withDCM(Pd(dba)₂) for bis(dibenzylideneacetone)palladiumRbf for round bottomed flask

RT for Retention Time.

SCX-2 for a silica-based sorbent with a chemically bonded propylsulfonicacid functional groupSFC for supercritical fluid chromatographyTBAF for tetra-n-butylammonium fluorideTBDMS for tert-butyldimethylsilylTFAA for trifluoroacetic anhydrideTFA for trifluoroacetic acidTHF for tetrahydrofuranTPP for tripotassium phosphateTs for toluenesulfonylXPhos-Pd-G1 for2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)chlorideXPhos-Pd-G2 forChloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

Analytical Methods

Commercially available starting materials, reagents and dry solventswere used as supplied. Flash column chromatography or glass columnchromatography was performed using Merck silica gel 230-400 mesh size.Flash chromatography was also performed on combi-flash RF Teledyne Iscomachine. Preparative TLC was performed on Merck plates.

Liquid Chromatography-Mass Spectrometry Methods Method-A

Waters Acquity UPLC with binary solvent manager, PDA detector andAcquity QDA performance mass detector, column: X-Bridge BEH C18, 50×2.1mm, 2.5 micron, column temperature: 35° C., auto sampler temperature: 5°C., mobile phase A: 0.1% (v/v) formic acid in water (pH=2.70), MobilePhase B: 0.1% formic acid (v/v) in water: acetonitrile (10:90), mobilephase gradient details: t=0 min (97% A, 3% B) flow: 0.8 mL/min; t=0.75min (97% A, 3% B) flow: 0.8 mL/min; gradient to t=2.7 min (2% A, 98% B)flow: 0.8 mL/min; gradient to t=3 min (0% A, 100% B) flow: 1 mL/min;t=3.5 min (0% A, 100% B) flow: 1 mL/min; gradient to t=3.51 min (97% A,3% B) flow: 0.8 mL/min; end of run at t=4 min (97% A, 3% B), Flow rate:0.8 mL/min, analysis time 4 min. Mass detector parameter: ionizationmode was cycled through positive and negative modes with cone voltage 10V and 30 V and 0.8 kV capillary voltage, temperature of source and probewere 120° C. and 600° C. respectively.

Method-B

Waters Acquity with PDA detector and SQ Detector, column: X-Bridge BEHC18, 50×2.1 mm, 2.5 micron, column temperature: 35° C., auto samplertemperature: 5° C., mobile phase A: 5 mM ammonium bicarbonate in water(pH=7.35), mobile phase B: acetonitrile; mobile phase gradient details:t=0 min (97% A, 3% B) flow: 0.5 mL/min; t=0.2 min (97% A, 3% B) flow:0.5 mL/min; gradient to t=2.7 min (2% A, 98% B) flow: 0.5 mL/min;gradient to t=3 min (0% A, 100% B) flow: 0.7 mL/min; t=3.5 min (0% A,100% B) flow: 0.7 mL/min; gradient to t=3.51 min (97% A, 3% B) flow: 0.5mL/min; end of run at t=4 min (97% A, 3% B), flow rate: 0.5 mL/min,analysis time 4 min. Mass detection parameter: ionization mode wascycled through positive and negative mode with cone voltage 10 V and 30V and 3.25 kV capillary voltage, temperature of source and probe were120° C. and 400° C. respectively.

Method-C

Waters Acquity UPLC with binary solvent manager, PDA detector andAcquity QDA performance mass detector, column: YMC Tri-art C18, 50×2 mm,1.9 micron, column temperature: 35° C., auto sampler temperature: 5° C.,mobile phase A: 0.1% (v/v) formic acid in water (pH=2.70), Mobile PhaseB: 0.1% formic acid (v/v) in water: acetonitrile (10:90), mobile phasegradient details: t=0 min (97% A, 3% B) flow: 0.8 mL/min; t=0.75 min(97% A, 3% B) flow: 0.8 mL/min; gradient to t=2.7 min (2% A, 98% B)flow: 0.8 mL/min; gradient to t=3 min (0% A, 100% B) flow: 1 mL/min;t=3.5 min (0% A, 100% B) flow: 1 mL/min; gradient to t=3.51 min (97% A,3% B) flow: 0.8 mL/min; end of run at t=4 min (97% A, 3% B), Flow rate:0.8 mL/min, analysis time 4 min. Mass detector parameter: ionizationmode was cycled through positive and negative modes with cone voltage 10V and 30 V and 0.8 kV capillary voltage, temperature of source and probewere 120° C. and 600° C. respectively.

Method-D

Waters Acquity UPLC with quaternary solvent manager, SQ detector andAcquity QDA mass detector, column: X-Bridge BEH C18, 50*2.1 mm, 2.5micron, column temperature: 35° C., auto sampler temperature: 5° C.,mobile phase A: 0.1% (v/v) Formic acid in water (pH=2.70), mobile phaseB: 0.1% (v/v) formic acid in water: acetonitrile (10:90), mobile phasegradient details: t=0 min (97% A, 3% B) flow: 0.8 mL/min; t=0.75 min(97% A, 3% B) flow: 0.8 mL/min; gradient to t=2.7 min (2% A, 98% B)flow: 0.8 mL/min; gradient to t=3 min (0% A, 100% B) flow: 1 mL/min;t=3.5 min (0% A, 100% B) flow: 1 mL/min; gradient to t=3.51 min (97% A,3% B) flow: 0.8 mL/min; end of run at t=4 min (97% A, 3% B), Flow rate:0.8 mL/min, analysis time 4 min. Mass detector parameter: ESI capillaryprobe, ionization mode cycled through positive and negative modes withcone voltage 10 V and 30V and 0.8 kV capillary voltage, temperature ofsource and probe were 120° C. and 400° C. respectively.

Method-E

Waters Acquity UPLC with binary solvent manager, PDA detector andAcquity QDA performance mass detector, column: Welch Xtimate C18, 50*2.1mm, 1.8 micron, column temperature: 35° C., auto sampler temperature: 5°C., mobile phase A: 0.1% (v/v) formic acid in water (pH=2.70), MobilePhase B: 0.1% formic acid (v/v) in water: acetonitrile (10:90), mobilephase gradient details: t=0 min (97% A, 3% B) flow: 0.8 mL/min; t=0.75min (97% A, 3% B) flow: 0.8 mL/min; gradient to t=2.7 min (2% A, 98% B)flow: 0.8 mL/min; gradient to t=3 min (0% A, 100% B) flow: 1 mL/min;t=3.5 min (0% A, 100% B) flow: 1 mL/min; gradient to t=3.51 min (97% A,3% B) flow: 0.8 mL/min; end of run at t=4 min (97% A, 3% B), Flow rate:0.8 mL/min, analysis time 4 min. Mass detector parameter: ionizationmode was cycled through positive and negative modes with cone voltage 10V and 30 V and 0.8 kV capillary voltage, temperature of source and probewere 120° C. and 600° C. respectively.

NMR

¹H Nuclear magnetic resonance (NMR) spectroscopy was carried out using aBruker Avance-400 instrument operating at 400 MHz using the statedsolvent at room temperature unless otherwise stated. Samples wereprepared as solutions in a suitable deuterated solvent and referenced tothe appropriate internal non-deuterated solvent peak ortetramethylsilane. Chemical shifts were recorded in ppm (δ) downfield oftetramethylsilane. In all cases, NMR data were consistent with theproposed structures. Characteristic chemical shifts (δ) are given inparts-per-million using conventional abbreviations for designation ofmajor peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd,doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad.

Purification Methods Preparative Purification by Reverse Phase HPLCPreparatory H PLC Method-A

Shimadzu Prep-20-AD with binary pump with UV/Visible wave-lengthdetector, Column: C18, 250×20 mm, 5 micron, column temperature: roomtemp., mobile phase A: 0.1% formic acid in water, mobile phase B:Acetonitrile: Methanol:2-Propanol(65:25:10); mobile phase gradientdetails: t=0 min (55% A, 45% B); t=17 min (55% A, 45% B); gradient tot=17.01 min (2% A, 98% B); t=19 min (2% A, 98% B); gradient to t=19.01min (55% A, 45% B); end of run at t=21 min (55% A, 45% B), flow rate: 27mL/min, analysis time 21 min.

Preparatory HPLC Method-B

Shimadzu Prep-20-AD with binary pump with UV/Visible wave-lengthdetector, Column: C18, 250*20 mm, 5 micron, column temperature: roomtemp., mobile phase A: 0.1% formic acid in water, mobile phase B:Acetonitrile; mobile phase gradient details: t=0 min (72% A, 28% B);t=19 min (72% A, 28% B); gradient to t=19.01 min (2% A, 98% B); t=21 min(2% A, 98% B); gradient to t=21.01 min (72% A, 28% B); end of run att=24 min (72% A, 28% B), flow rate: 20 mL/min, analysis time 24 min.

Preparatory HPLC Method-C

Shimadzu LC20AP purification system with UV detector. Column: YMC-ActusTriart prep 250*20 mm, 5 micron, room temperature. Compounds elutedwith: Mobile phase A: 0.1% Formic acid in Milli Q water, mobile phase B:Acetonitrile; mobile phase gradient details: t=0 min (65% A, 35% B);gradient to t=17 min (35% A, 65% B); t=17.01 min (2% A, 98% B); gradientto t=19 min (2% A, 98% B); t=19.01 min (65% A, 35% B) to t=21 min (65%A, 35% B); ); flow rate=20 ml/min; analysis time 21 min.

Chiral Prep HPLC Purification Methods

The enantiomeric separation of compounds was achieved by Chiral PrepHPLC purification methods.

Below is a list of Chiral Prep HPLC purification methods and conditionsused to resolve enantiomers or to determine enantiomeric purity (ee).

Chiral Prep HPLC purification methods Conditions for chiral resolutionor ee determination Method-A Waters binary gradient with 600-controllerpump with Waters 2487-UV/Visible wave-length detector, Column:YMC-CHIRAL ART CELLULOSE-SC, 250*20 mm, 5 micron, column temperature:room temp., mobile phase A: n-Heptane, mobile phase B: 2-propanol; withisocratic flow A:B~70:30, flow rate: 17 mL/min, analysis time 55 min.

Synthesis

Several methods for the chemical synthesis of heterocyclic carboxamidecompounds of the present application are described herein. These and/orother well-known methods may be modified and/or adapted in various waysto facilitate the synthesis of additional compounds within the scope ofthe present application and claims. Such alternative Methods andmodifications should be understood as being within the spirit and scopeof this application and claims. Accordingly, Methods set forth in thefollowing descriptions, Schemes and Examples are intended forillustrative purposes and are not to be construed as limiting the scopeof the disclosure.

In one approach (Scheme 1), compounds of formula [I] may be prepared bythe reaction of a substituted aromatic carboxylic acid of formula [II]with oxalyl chloride or thionyl chloride in a solvent such as DCM, withan amine of general formula [III] in the presence of a tertiary aminebase such as Et₃N, DIPEA or NMM. The reaction is suitably conducted atRT. After reaction work up, typically by liquid-liquid extraction, thereaction product is purified by flash column chromatography, reversephase preparative HPLC or re-crystallisation (Method A). Compounds ofcompounds of formula [I] may also be prepared by the reaction of asubstituted aromatic carboxylic acid of formula [II] with an amine ofgeneral formula [III] and a suitable coupling agent such as HBTU or HATUin a polar aprotic solvent such as DMA or DMF in the presence of atertiary amine base such as Et₃N, DIPEA or NMM. After reaction work up,typically by liquid-liquid extraction, the reaction product is purifiedby flash column chromatography, reverse phase preparative HPLC orre-crystallisation (Method B). The bis-tosyl protected intermediate(from Method A or B) is then subject to base induced deprotection with asuitable base such as K₂CO₃ or KOH in a suitable protic solvent such asMeOH or EtOH. The reaction is suitably conducted at high temperature.After reaction work up, typically by liquid-liquid extraction, thereaction product is purified by flash column chromatography, reversephase preparative HPLC or re-crystallisation, to yield compounds ofgeneral the Formula [I]

Example 1:[2,4-dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone

Method 1 Step-1:5-(pyrimidin-2-ylmethoxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 40)

To a solution of 2-(pyrimidin-2-ylmethoxy)-4,6-bis(tosyloxy)benzoic acid(Intermediate 25) (0.3 g, 0.525 mmol, 1 eq) in DMF (3 mL) were addedHATU (0.29 g, 0.788 mmol, 1.5 eq), DIPEA (0.135 g, 1.051 mmol, 2.0 eq)and pyrrolidine (0.041 g, 0.578 mmol, 1.0 eq) at 0° C. under a nitrogenatmosphere. The reaction mixture was stirred at 0° C. for 30 min. Theresulting reaction mixture was diluted with water (40 mL) and extractedwith ethyl acetate (4×50 mL). The combined organic layer was dried overNa₂SO₄ and concentrated under vacuum. The crude material was purified byflash chromatography (product eluted with 15% MeOH in DCM) yielding5-(pyrimidin-2-ylmethoxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 40) (0.19 g, 58% yield).

¹H NMR (DMSO-d6, 400 MHz): δ 1.73-1.75 (m, 4H), 2.42 (s, 3H), 2.45 (s,3H), 3.40-3.50 (m, 4H), 5.26 (d, J=3.2 Hz, 2H), 6.54 (d, J=1.6 Hz, 1H),6.70 (d, J=2.0 Hz, 1H), 7.43-7.53 (m, 5H), 7.65-7.41 (m, 4H), 8.80 (d,J=4.8 Hz, 2H). LCMS (Method A): 2.204 min, MS: ES+624.20 (M+1)

Step-2:(2,4-dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl)(pyrrolidin-1-yl)methanone

To a solution of5-(pyrimidin-2-ylmethoxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 40) (0.6 g, 0.481 mmol, 1eq) in EtOH (0.6 mL) was added dropwise a solution of KOH (1.07 g, 19.24mmol, 40 eq) in water (0.5 mL) at room temperature. The reaction mixturewas heated at 80° C. for 2 h cooled, poured into ice-cold water (80 mL)and extracted with ethyl acetate (4×80 mL). The combined organic layerwas dried over Na₂SO₄ and concentrated under vacuum. The crude materialwas purified by flash chromatography (product eluted with 7% MeOH inDCM) yielding(2,4-dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl)(pyrrolidin-1-yl)methanone(0.045 g, 15% Yield).

¹H NMR (DMSO-d6, 400 MHz): δ 1.75-1.81 (m, 4H), 3.21-3.23 (m, 2H),3.31-3.33 (m, 2H), 5.16 (s, 2H), 5.79 (d, J=1.6 Hz, 1H), 5.92 (d, J=2.0Hz, 1H), 7.45 (t, J=3.5 Hz, 1H), 8.82 (d, J=4.8 Hz, 2H), 9.36 (s, 1H),9.41 (s, 1H). LCMS (Method A): 1.033 min, MS: ES+316.16 (M+1)

Example 2:(2-(cyclopentyloxy)-4,6-dihydroxyphenyl)(pyrrolidin-1-yl)methanone

Method 2 Step-1: Synthesis of5-(cyclopentyloxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 41)

To a solution of 2-(cyclopentyloxy)-4,6-bis(tosyloxy)benzoic acid(Intermediate 20) (0.5 g, 0.91 mmol, 1 eq) in DCM (5 mL) was addeddropwise oxalyl chloride (0.13 g, 1.02 mmol, 1.0 eq) at 0° C. undernitrogen atmosphere. A catalytic amount of DMF (0.5 mL) was added to thereaction mixture at 0° C., and the reaction mixture was slowly warmed toroom temperature and stirred for 2 h. The resulting mixture wasconcentrated under reduce pressure to obtained crude acid chloride. Inanother Rbf, a solution of pyrrolidine in THF (0.130 g, 1.83 mmol, 2.0eq) was treated with TEA (0.18 g, 1.78 mmol, 2.0 eq) at 0° C. Crude acidchloride in DCM (5 mL) was added dropwise to the amine solution at 0° C.The reaction mixture was stirred at 0° C. for 30 min. The reactionmixture diluted with water (20 mL) and extracted in DCM (3×50 mL). Thecombined organic layer was washed with saturated NaHCO₃ solution (2×20mL), dried over Na₂SO₄ and concentrated under vacuum yielding5-(cyclopentyloxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 41) as a brown oil (0.4 g,72% yield). The crude material was used in the next step withoutpurification.

¹H NMR (DMSO-d6, 400 MHz): 1.37-1.44 (m, 2H), 1.53-1.55 (m, 4H),1.65-1.80 (m, 6H), 2.43-2.45 (m, 6H), 2.50-2.51 (m, 1H), 2.83-2.94 (m,1H), 3.24-3.40 (m, 2H), 4.60-4.70 (m, 1H), 6.57-6.60 (m, 2H), 7.48-7.54(m, 4H), 7.73-7.77 (m, 4H). LCMS (Method A): 2.509 min, MS: ES+600.15(M+1)

Step-2:(2-(cyclopentyloxy)-4,6-dihydroxyphenyl)(pyrrolidin-1-yl)methanone

To a solution of5-(cyclopentyloxy)-4-(pyrrolidine-1-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 41) (0.2 g, 0.33 mmol, 1 eq)in MeOH (4 mL) was added KOH (0.74 g, 13.19 mmol, 40 eq) at roomtemperature. The reaction mixture was heated at 60° C. for 2 h. Theresulting reaction mixture was poured into water (30 mL), acidifiedusing saturated solution of KHSO₄ and extracted with ethyl acetate (4×50mL). The combined organic layer was dried over Na₂SO₄ and concentratedunder vacuum. The crude material was purified by flash chromatography(product eluted with 20% EtOAc in n-Hexane) yielding(2-(cyclopentyloxy)-4,6-dihydroxyphenyl)(pyrrolidin-1-yl)methanone(0.030 g, 30.9% Yield).

¹H NMR (DMSO-d6, 400 MHz): δ 1.53-1.64 (m, 6H), 1.71-1.82 (m, 6H), 3.05(t, J=6.4 Hz, 2H), 3.32-3.34 (m, 2H), 4.64-4.66 (m, 1H), 5.86-5.91 (m,2H), 9.30-9.34 (m, 2H). LCMS (Method A): 1.434 min, MS: ES+292.06 (M+1).

The following compounds were prepared according to the Methods describedabove using the indicated intermediates

Ex. No. Name Structure Data  3 (2-benzyloxy- 4,6-dihydroxy- phenyl)-pyrrolidin-1-yl- methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.74-1.82 (m, 4H), 3.10-3.13 (m, 2H),3.36-3.38 (m, 2H), 5.03 (s, 2H), 5.97 (s, 2H), 7.31-7.40 (m, 5H), 9.50(s, 2H). LCMS (Method A): 1.515 min, MS: ES+ 314.11 (M + 1) UsingIntermediate 21 and pyrrolidine according to Method 2  4 (2-benzyloxy-4,6-dihydroxy- phenyl)- isoindolin-2-yl- methanone

¹H NMR (DMSO-d6, 400 MHz): δ 4.49 (s, 2H), 4.74 (s, 2H), 5.04 (s, 2H),6.01 (s, 2H), 7.24-7.31 (m, 8H), 7.37-7.39 (m, 1H), 9.50 (s, 1H), 9.57(s, 1H). LCMS (Method A): 1.719 min, MS: ES+ 362.17 (M + 1) UsingIntermediate 21 and 2,3- dihydro-1H-isoindole according to Method 2  5(2-benzyloxy- 4,6-dihydroxy- phenyl)-(1- piperidyl) methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.38-1.53 (m, 6H), 3.15-3.16 (m, 2H),3.40-3.41 (m, 1H), 3.61-3.63 (m, 1H), 4.99 (s, 2H), 5.95 (s, 2H),7.30-7.31 (m, 1H), 7.37-7.38 (m, 4H), 9.37 (s, 1H), 9.40 (s, 1H). LCMS(Method A): 1.632 min, MS: ES+ 328.17 (M + 1) Using Intermediate 21 andpiperidine according to Method 2  6 (2-benzyloxy- 4,6-dihydroxy-phenyl)-[(3S)-3- hydroxypyrrolidin- 1-yl]methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.72-1.90 (m, 2H), 2.95-3.17 (m, 1H),3.26-3.29 (m, 1H), 3.41-3.51 (m, 2H), 4.20-4.29 (m, 1H), 4.92- 4.95 (m,1H), 5.01 (s, 2H), 5.95 (s, 2H) 7.29-7.37 (m, 5H), 9.41 (s, 2H). LCMS(Method A): 1.192 min, MS: ES+ 330.12 (M + 1) Using Intermediate 21 and(3S)-3- pyrrolidinol according to Method 1. Note: Duplication of peaksobserved in the ¹H NMR-material is a mixture of rotamers.  7(2-benzyloxy- 4,6-dihydroxy- phenyl)-[(3R)-3- hydroxypyrrolidin-1-yl]methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.72-1.90 (m, 2H), 2.95-3.17 (m, 1H),3.26-3.29 (m, 1H), 3.41-3.51 (m, 2H), 4.20-4.29 (m, 1H), 4.92- 4.95 (m,1H), 5.01 (s, 2H), 5.95 (s, 2H) 7.29-7.37 (m, 5H), 9.41-9.44 (m, 2H).LCMS (Method A): 1.180 min, MS: ES+ 330.17 (M + 1) Using Intermediate 21and (3R)-3- pyrrolidinol according to Method 1. Note: Duplication ofpeaks observed in the ¹H NMR-material is a mixture of rotamers.  8(2-benzyloxy- 4,6-dihydroxy- phenyl)-[(3R)-3- hydroxy-1- piperidyl]methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.14-2.08 (m, 6H), 3.29-3.25 (m, 1H),3.38-3.50 (m, 1H), 4.31-4.42 (m, 1H), 4.78-4.93 (m, 1H), 4.99 (d, J =11.2 Hz, 2H), 5.93-5.96 (m, 2H) 7.29-7.38 (m, 5H), 9.39-9.42 (m, 2H).LCMS (Method A): 1.305 min, MS: ES+ 344.17 (M + 1) Using Intermediate 21and (R)-3- hydroxypiperidine according to Method 1. Note: Duplication ofpeaks observed in the ¹H NMR-material is a mixture of rotamers.  9(2-benzyloxy- 4,6-dihydroxy- phenyl)-[(3S)-3- hydroxy-1- piperidyl]methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.14-2.08 (m, 6H), 3.29-3.25 (m, 1H),3.38-3.50 (m, 1H), 4.31-4.42 (m, 1H), 4.78-4.93 (m, 1H), 4.99 (d, J =11.2 Hz, 2H), 5.93-5.96 (m, 2H) 7.29-7.38 (m, 5H), 9.39-9.42 (m, 2H).LCMS (Method A): 1.302 min, MS: ES+ 344.17 (M + 1) Using Intermediate 21and (S)-3- hydroxypiperidine according to Method 1. Note: Duplication ofpeaks observed in the ¹H NMR-material is a mixture of rotamers. 10(2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- pyrrolidin-1-yl-methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.73-1.75 (m, 4H), 1.94 (s, 3H), 3.01- 3.17(m, 2H), 3.34-3.39 (m, 2H), 4.68-4.70 (m, 1H), 4.86-4.88 (m, 1H), 6.24(s, 1H), 7.31-7.39 (m, 5H), 9.35 (s, 1H), 9.44 (s, 1H). LCMS (Method A):1.638 min, MS: ES+ 328.17 (M + 1). Using Intermediate 22 and pyrrolidineaccording to Method 1 11 (2-benzyloxy-3- ethyl-4,6- dihydroxy- phenyl)-pyrrolidin-1-yl- methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.03 (t, J = 7.2 Hz, 3H), 1.73-1.75 (m,4H), 3.13-3.16 (m, 2H), 3.34-3.40 (m, 2H), 4.68-4.70 (m, 1H), 4.90- 4.92(m, 1H), 6.23 (s, 1H), 6.32 (s, 1H), 6.55 (s, 6H), 7.32-7.41 (m, 5H),9.34 (s, 1H), 9.41 (s, 1H). LCMS (Method A): 1.776 min, MS: ES+ 342.17(M + 1). Using Intermediate 23 and pyrrolidine according to Method 2 12[2,4-dihydroxy- 6-(2- pyridylmethoxy) phenyl]- pyrrolidin-1-yl-methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.73-1.83 (m, 4H), 3.14 (t, J = 6.4 Hz,2H), 3.40 (t, J = 6.8 Hz, 2H), 5.08 (s, 2H), 5.92 (d, J = 1.6 Hz, 1H),5.96 (d, J = 1.6 Hz, 1H), 7.31 (dd, J = 6.8, 4.8 Hz, 1H), 7.39 (d, J =8.0 Hz, 1H), 7.81-7.85 (m, 1H), 8.55 (d, J = 4.0 Hz, 1H), 9.44 (s, 1H),9.47 (s, 1H). LCMS (Method A): 0.959 min, MS: ES+ 315.11 (M + 1) UsingIntermediate 24 and pyrrolidine according to Method 1 13 [2,4-dihydroxy-6-1- phenylethoxy] phenyl]-pyrrolidin- 1-yl-methanone ISOMER 1

¹H NMR (DMSO-d6, 400 MHz): δ 1.42 (d, J = 7.6 Hz, 3H), 1.75-1.81 (m,4H), 3.04-3.11 (m, 2H), 3.35- 3.40 (m, 2H), 5.28-5.33 (m, 1H), 5.77 (s,1H), 5.87 (d, J = 1.6 Hz, 1H), 7.23-7.28 (m, 1H), 7.31-7.34 (m, 4H),9.44 (s, 2H). LCMS (Method A): 1.660 min, MS: ES+ 328.20 (M + 1) UsingIntermediate 26 and pyrrolidine according to Method 1 Separated bychiral Prep HPLC (Method A) 14 [2,4-dihydroxy- 6-1- phenylethoxy]phenyl]-pyrrolidin- 1-yl-methanone ISOMER 2

¹H NMR (DMSO-d6, 400 MHz): δ 1.42 (d, J = 7.6 Hz, 3H), 1.75-1.81 (m,4H), 3.04-3.11 (m, 2H), 3.35- 3.40 (m, 2H), 5.28-5.33 (m, 1H), 5.77 (s,1H), 5.87 (d, J = 1.6 Hz, 1H), 7.23-7.28 (m, 1H), 7.31-7.34 (m, 4H),9.44 (s, 2H). LCMS (Method A): 1.661 min, MS: ES+ 328.20 (M + 1) UsingIntermediate 26 and pyrrolidine according to Method 1 Separated bychiral Prep HPLC (Method A) 15 [2-[(4- fluorophenyl) methoxy]-4,6-dihydroxy- phenyl]- pyrrolidin-1-yl- methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.72-1.81 (m, 4H), 3.09 (t, J = 6.0 Hz,2H), 3.65 (t, J = 6.4 Hz, 2H), 5.00 (s, 2H), 5.96 (s, 2H), 7.19-7.22 (m,2H), 7.38-7.42 (m, 2H), 9.42 (s, 2H). LCMS (Method A): 1.504 min, MS:ES+ 332.17 (M + 1) Using Intermediate 27 and pyrrolidine according toMethod 2 16 [2,4-dihydroxy- 6-[(4- methoxyphenyl) methoxy]phenyl]-pyrrolidin-1-yl- methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.72-1.81 (m, 4H), 3.08 (t, J = 6.4 Hz,2H), 3.34-3.36 (m, 2H), 3.74 (s, 3H), 4.92 (s, 2H), 5.94-5.96 (m, 2H),6.92 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 9.40 (s, 2H). LCMS(Method A): 1.465 min, MS: ES+ 344.20 (M + 1) Using Intermediate 28 andpyrrolidine according to Method 2 17 [2,4-dihydroxy- 6-(m- tolylmethoxy)phenyl]-pyrrolidin- 1-yl-methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.74-1.82 (m, 4H), 2.30 (s, 3H), 3.09- 3.12(t, J = 12.0 Hz, 2H), 3.36-3.39 (t, J = 12.0 Hz, 2H), 4.95 (s, 2H),5.94- 5.95 (d, J = 3.6 Hz, 2H), 7.10-7.16 (m, 3H), 7.23-7.27 (t, J =14.8 Hz, 1H), 9.41 (s, 1H). LCMS (Method A): 1.598 min, MS: ES⁺ 328.2(M + 1) Using Intermediate 29 and pyrrolidine according to Method 2 18(2-benzyloxy- 4,6-dihydroxy- phenyl)-(5,7- dihydropyrrolo[3,4-b]pyridin-6- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 4.44-4.52 (m, 2H), 4.70-4.78 (m, 2H), 5.04(s, 2H), 6.02 (s, 2H), 7.23- 7.33 (m, 6H), 7.69-7.81 (m, 1H), 8.44-8.47(dd, J = 12.4 Hz, 1H), 9.53- 9.54 (d, J = 5.2 Hz, 1H), 9.61-9.62 (d, J =2.4 Hz, 1H). LCMS (Method A): 1.338 min, MS: ES⁺ 363.2 (M + 1) UsingIntermediate 21 and 6,7- dihydro-5H-pyrrolo[3,4-b]pyridine according toMethod 2 19 (2-benzyloxy- 4,6-dihydroxy- phenyl)-(4- methoxyisoindolin-2-yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 3.74-3.83 (m, 3H), 4.33-4.47 (m, 2H),4.61-4.73 (m, 2H), 5.04 (s, 2H), 6.011-6.016 (d, J = 2.0 Hz, 2H), 6.83-6.97 (m, 2H), 7.24-7.32 (m, 6H), 9.51-9.53 (d, J = 7.6 Hz, 1H), 9.58-9.59 (d, J = 5.2 Hz, 1H). LCMS (Method A): 1.773 min, MS: ES⁺ 392.2(M + 1) Using Intermediate 21 and 2,3- Dihydro-4-methoxy-1H-isoindoleaccording to Method 1 20 [2,4-dihydroxy- 6-(pyrimidin-4-ylmethoxy)phenyl]- pyrrolidin-1- yl-methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.77-1.85 (m, 4H), 3.14-3.18 (t, J = 13.2Hz, 2H), 3.42-3.44 (t, J = 6.0 Hz, 2H), 5.12 (s, 2H), 5.89-5.90 (d, J =2.0 Hz, 2H), 6.020-6.024 (d, J = 1.6 Hz, 2H), 7.48-7.49 (d, J = 4.0 Hz,1H), 8.83-8.85 (d, J = 5.2 Hz, 1H), 9.156-9.159 (d, J = 1.2 Hz, 2H),9.52 (s, 1H), 9.60 (s, 1H). LCMS (Method A): 1.138 min, MS: ES⁺ 316.2(M + 1) Using Intermediate 30 and pyrrolidine according to Method 1 21(2-((1H-pyrazol- 3-yl)methoxy)- 4,6- dihydroxyphenyl) (pyrrolidin-1-yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.71-1.79 (m, 4H), 3.05-3.08 (m, 2H),3.08-3.31 (m, 2H), 4.94 (s, 2H), 5.94 (s, 1H), 6.03 (d, J = 1.6 Hz, 1H),6.21 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 9.39 (s, 1H), 9.42 (s, 1H),12.78 (s, 1H). LCMS (Method A): 1.046 min, MS: ES+ 304.11 (M + 1) UsingIntermediate 31 and pyrrolidine according to Method 1 (Boc- deprotectionoccurred in situ) 22 [2,4-dihydroxy- 6-(1H-triazol-4- ylmethoxy)phenyl]-pyrrolidin-1- yl-methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.70-1.78 (m, 4H), 3.03-3.06 (t, J = 12.8Hz, 2H), 3.30-3.33 (t, J = 13.2 Hz, 2H), 5.08 (s, 2H), 5.95-5.96 (d, J =2.0 Hz, 1H), 6.054-6.059 (d, J = 2.0 Hz, 2H), 7.82 (s, 1H), 9.44 (s,2H), 14.99 (s, 1H). LCMS (Method B): 1.084 min, MS: ES⁺ 305.1 (M + 1)Using Intermediate 36 and pyrrolidine according to Method 1 23(2-benzyloxy- 4,6-dihydroxy- phenyl)-(5- bromoisoindolin- 2-yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 4.43-4.48 (m, 2H), 4.68-4.73 (m, 2H), 5.03(s, 2H), 6.00 (s, 2H), 7.22- 7.53 (m, 6H), 7.45-7.61 (m, 2H), 9.51 (s,1H), 9.59 (s, 1H). LCMS (Method A): 2.123 min, MS: ES⁺ 440 (M+) UsingIntermediate 21 and 5-bromo- 2,3-dihydro-1H-isoindole according toMethod 1 24 methyl 2-(2- benzyloxy-4,6- dihydroxy- benzoyl)isoindoline-5-carboxylate

¹H NMR (DMSO-d6, 400 MHz): δ 3.83-3.86 (m, 3H), 4.54 (s, 2H), 4.79 (s,2H), 5.03 (s, 2H), 6.01 (s, 2H), 7.22-7.29 (m, 5H), 7.39-7.53 (m, 1H),9.86-7.98 (m, 2H), 9.516- 9.519 (d, J = 1.2 Hz, 1H), 9.59-9.60 (d, J =2.4 Hz, 1H). LCMS (Method A): 1.699 min, MS: ES⁺ 420.2 (M + 1) UsingIntermediate 21 and methyl isoindoline-5-carboxylate according to Method1 25 (2-benzyloxy- 4,6-dihydroxy- phenyl)-(5- methoxyisoindolin-2-yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 3.70-3.75 (d, 3H), 4.40-4.44 (d, 2H),4.65-4.69 (d, 2H), 5.03 (s, 2H), 6.00 (s, 2H), 6.82-6.96 (m, 2H), 7.14-7.30 (m, 6H), 9.494-9.499 (d, J = 2.0 Hz, 1H), 9.565-9.576 (d, J = 4.4Hz, 1H). LCMS (Method D): 1.980 min, MS: ES⁺ 392.5 (M + 1) UsingIntermediate 21 and 5- methoxyisoindoline according to Method 1 26(2-benzyloxy- 4,6-dihydroxy- phenyl)-(5,6- dimethoxyisoindolin-2-yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 3.68 (s, 3H), 3.75 (s, 3H), 4.39 (s, 2H),4.65 (s, 2H), 5.03 (s, 2H), 6.004- 6.007 (d, J = 1.2 Hz, 2H), 6.86 (s,1H), 6.98 (s, 1H), 7.23-7.31 (m, 5H), 9.49 (s, 1H), 9.56 (s, 1H). LCMS(Method D): 1.836 min, MS: ES⁺ 422.5 (M + 1) Using Intermediate 21 and5,6- dimethoxyisoindoline according to Method 1 27 [2,4-dihydroxy- 6-(1-phenylethoxy) phenyl]-isoindolin- 2-yl-methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.375-1.391 (d, J = 6.4 Hz, 3H), 4.48 (s,2H), 4.75-4.78 (d, J = 3.2 Hz, 2H), 5.33-5.35 (d, J = 6.4 Hz, 2H), 5.85(s, 1H), 5.941-5.945 (d, J = 1.6 Hz, 2H), 7.20-7.40 (m, 9H), 9.389 (s,1H), 9.525 (s, 1H). LCMS (Method A): 1.925 min, MS: ES⁺ 398.2 (M + 23)Using Intermediate 26 and isoindoline according to Method 1 28[2,4-dihydroxy- 6-(1- phenylethoxy) phenyl]-(5- methoxyisoindolin-2-yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.374-1.388 (d, J = 5.6 Hz, 3H), 3.71- 3.76(d, 3H), 4.42 (s, 2H), 4.46-4.77 (m, 2H), 5.33-5.34 (d, J = 5.6 Hz, 1H),5.82 (s, 1H), 5.94 (s, 1H), 6.83- 7.29 (m, 8H), 9.380 (s, 1H), 9.507 (s,1H). LCMS (Method D): 2.040 min, MS: ES⁺ 406.4 (M + 1) UsingIntermediate 26 and 5- methoxyisoindoline according to Method 1 29[2,4-dihydroxy- 6-(1- phenylethoxy) phenyl]-(5,6- dimethoxyisoindolin-2-yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 3.696 (s, 3H), 3.762 (s, 3H), 4.40 (s, 2H),4.69 (s, 2H), 5.33-5.34 (d, J = 6.4 Hz, 1H), 5.844 (s, 1H), 5.937 (S,1H), 6.86 (s, 1H), 7.00 (s, 1H), 7.21- 729 (m, 5H), 9.36 (s, 1H), 9.49(s, 1H). LCMS (Method A): 1.738 min, MS: ES⁺ 436.1 (M + 1) UsingIntermediate 26 and 5,6- dimethoxyisoindoline according to Method 1 30(2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- (5,7- dihydropyrrolo[3,4-b]pyridin-6- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.96 (s, 3H), 4.34-4.60 (m, 2H), 4.67- 4.78(m, 3H), 4.90-4.92 (d, J = 10.4 Hz, 1H), 6.30 (s, 1H), 7.21-7.35 (m,6H), 7.66-7.81 (m, 1H), 8.41- 8.46 (dd, J = 14.0 Hz, 1H), 9.59 (s, 2H).LCMS (Method A): 1.492 min, MS: ES⁺ 477.3 (M + 1) Using Intermediate 22and 6,7- dihydro-5H-pyrrolo[3,4-b]pyridine according to Method 1 31 5,7-dihydropyrrolo[3,4- b]pyridin-6-yl- [4,6-dihydroxy- 3-methyl-2-(m-tolylmethoxy) phenyl]methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.98 (s, 3H), 2.16 (s, 3H), 4.35-4.81 (m,5H), 4.86-4.89 (d, J = 10.4 Hz, 1H), 6.30 (s, 1H), 7.018-7.035 (d, J =6.8 Hz, 1H), 7.12-7.18 (m, 3H), 7.27-7.33 (m, 1H), 8.42-8.47 (dd, J =18.4 Hz, 1H), 9.52-9.54 (d, J = 7.6 Hz, 1H), 9.58-9.59 (d, J = 4.8 Hz,1H). LCMS (Method A): 1.584 min, MS: ES⁺ 391.1 (M + 1) UsingIntermediate 33 and 6,7- dihydro-5H-pyrrolo[3,4-b]pyridine according toMethod 1 32 5,7- dihydropyrrolo[3,4- b]pyridin-6-yl- [2,4-dihydroxy-6-(m- tolylmethoxy) phenyl]methanone

¹H NMR (DMSO-d6, 400 MHz): δ 2.07-2.10 (m, 3H), 4.43-4.51 (d, 2H),4.70-4.78 (d, 2H), 4.99 (s, 2H), 6.02 (s, 2H), 7.00-7.14 (m, 4H), 7.28-7.34 (m, 1H), 7.69-7.83 (m, 1H), 8.43-8.48 (dd, J = 12.8 Hz, 1H), 9.55(s, 1H), 9.62 (s, , 1H). LCMS (Method A): 1.454 min, MS: ES⁺ 377.2(M + 1) Using Intermediate 29 and 6,7- dihydro-5H-pyrrolo[3,4-b]pyridineaccording to Method 1 33 5,7- dihydropyrrolo[3,4- b]pyridin-6-yl-[4,6-dihydroxy- 3-methyl-2-(2- pyridylmethoxy) phenyl]methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.97 (s, 3H), 4.40-4.69 (m, 4H), 4.80- 5.03(m, 2H), 6.32 (s, 2H), 7.22- 7.33 (m, 2H), 7.46-7.49 (dd, , J = 7.6 Hz,1H), 7.68-7.80 (m, 2H), 8.41- 8.46 (m, 2H), 9.58-9.63 (m, 2H). LCMS(Method A): 1.029 min, MS: ES⁺ 378.1 (M + 1) Using Intermediate 34 and6,7- dihydro-5H-pyrrolo[3,4-b]pyridine according to Method 1 34[4,6-dihydroxy- 3-methyl-2-(2- pyridylmethoxy) phenyl]- isoindolin-2-yl-methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.96 (s, 3H), 4.46-4.75 (m, 4H), 4.79- 5.03(m, 2H), 6.31 (s, 2H), 7.23- 7.30 (m, 4H), 7.34-7.36 (d, J = 6.8 Hz,1H), 7.46-7.48 (d, J = 7.6 Hz, 1H), 7.72-7.76 (m, 1H), 8.43-8.44 (d, J =4.8 Hz, 1H), 9.54 (s, 1H), 9.58 (s, 1H). LCMS (Method A): 1.337 min, MS:ES⁺ 377.2 (M + 1) Using Intermediate 34 and isoindoline according toMethod 1 35 5,7- dihydropyrrolo[3,4- b]pyridin-6-yl- [2,4-dihydroxy-6-(2- pyridylmethoxy) phenyl]methanone

¹H NMR (DMSO-d6, 400 MHz): δ 4.52-4.59 (d, 2H), 4.73-4.81 (d, 2H), 5.10(s, 2H), 6.03-6.05 (m, 2H), 7.22-7.28 (m, 2H), 7.35-7.37 (d, J = 8.0 Hz,1H), 7.66-7.69 (t, J = 13.6 Hz, 2H), 8.45-8.46 (d, J = 4.4 Hz, 1H), 9.34(s, 1H), 9.38 (s, 1H). LCMS (Method A): 0.926 min, MS: ES⁺ 364.1 (M + 1)Using Intermediate 24 and 6,7- dihydro-5H-pyrrolo[3,4-b]pyridineaccording to Method 1 36 (2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)-(3,4-dihydro-1H- isoquinolin-2- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.92-1.95 (d, 3H), 2.70-2.83 (m, 2H),3.38-4.01 (m, 2H), 4.40-4.69 (m, 2H), 4.76-4.85 (m, 2H), 6.26- 6.28 (m,2H), 7.01-7.30 (m, 9H), 9.41 (s, 1H), 9.52 (s, 1H). LCMS (Method A):1.977 min, MS: ES⁺ 390.2 (M + 1) Using Intermediate 22 and 1,2,3,4-tetrahydroisoquinoline according to Method 1. Note: Duplication of peaksobserved in the ¹H NMR-material is a mixture of rotamers. 37[2,4-dihydroxy- 6-(2- pyridylmethoxy) phenyl]- isoindolin-2-yl-methanone

¹H NMR (DMSO-d6, 400 MHz): δ 4.54 (s, 2H), 2.76 (s, 2H), 5.10 (s, 2H),5.96-5.96 (d, J = 2.0 Hz, 1H), 6.014-6.018 (d, J = 1.6 Hz, 1H), 7.24-7.39 (m, 6H), 7.67-7.72 (m, 1H), 8.48-8.49 (d, J = 4.0 Hz, 1H), 9.51 (s,1H), 9.62 (s, 1H). LCMS (Method A): 1.278 min, MS: ES⁺ 363.1 (M + 1)Using Intermediate 24 and Isoindoline according to Method 1 38(2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- (4- bromoisoindolin-2-yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.97-1.99 (d, 3H), 4.27-4.75 (m, 4H),4.84-4.95 (m, 2H), 6.30-6.31 (d, J = 2.4 Hz, 1H), 7.25-7.41 (m, 7H),7.47-7.52 (m, 1H), 9.52-9.60 (m, 2H). LCMS (Method D): 2.379 min, MS:ES⁺ 354.4 (M + 1) Using Intermediate 22 and 4- bromoisoindolineaccording to Method 1. Note: Duplication of peaks observed in the ¹HNMR-material is a mixture of rotamers. 39 (2-benzyloxy- 4,6-dihydroxy-3-methyl-phenyl)- [4- (hydroxymethyl) isoindolin-2- yl]methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.97-1.98 (d, 3H), 4.33-4.34 (d, 1H),4.42-4.64 (m, 3H), 4.72-4.74 (d, 3H), 4.91-4.93 (d, 1H), 5.07- 5.21 (m,1H), 6.30 (S, 1H), 7.13-7.37 (m, 8H), 9.49-9.55 (m, 2H). LCMS (MethodA): 1.571 min, MS: ES⁺ 406.1 (M + 1) Using Intermediate 22 and 2,3-dihydro-1H-isoindole-4-methanol according to Method 1. Note: Duplicationof peaks observed in the ¹H NMR-material is a mixture of rotamers. 40(2-benzyloxy- 4,6-dihydroxy-3- methyl-phenyl)- [5-[(4- methylpiperazin-1-yl)methyl] isoindolin-2- yl]methanone

¹H NMR (DMSO-d6, 400 MHz): 1.23 (s, 3H), 2.12 (d, J = 8.0 Hz, 3H), 2.20-2.30 (m, 4H), 2.30-2.40 (m, 4H), 3.36-3.40 (m, 2H), 4.40-44 (m, 1H),4.54-4.57 (m, 1H), 4.71-4.73 (m, 3H), 4.89-4.92 (m, 1H), 6.31 (s, 1H),7.14-7.31 (m, 8H), 9.53-9.60 (m, 2H). LCMS (Method A): 1.250 min, MS:ES⁺ 488.3 (M + 1) Using Intermediate 22 and 2,3- dihydro-5-[(4-methyl-1-piperazinyl)methyl]-1H-isoindole according to Method 1 41 (2-benzyloxy-4,6-dihydroxy-3- methyl-phenyl)- (6-methoxy-3,4- dihydro-1H-isoquinolin-2- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.92-1.95 (d, 3H), 2.68-2.73 (m, 2H),3.70-3.71 (d, 3H), 3.96-4.85 (m, 6H), 6.26-6.28 (m, 1H), 6.68- 6.71 (m,1H), 6.79-6.95 (m, 1H), 7.16-7.29 (m, 5H), 9.38-9.40 (d, 1H), 9.52 (s,1H). LCMS (Method A): 1.888 min, MS: ES⁺ 420.2 (M + 1) UsingIntermediate 22 and 6- methoxy-1,2,3,4- tetrahydroisoquinoline accordingto Method 1. Note: Duplication of peaks observed in the ¹H NMR-materialis a mixture of rotamers. 42 (2-benzyloxy- 4,6-dihydroxy-3-methyl-phenyl)- (3,4-dihydro-1H- 2,7- naphthyridin-2- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.93-1.96 (d, 3H), 2.74-2.79 (m, 2H),3.44-3.45 (m, 1H), 3.68-4.98 (m, 1H), 4.46 (s, 1H), 4.58-4.89 (m, 3H),6.27-6.29 (m, 1H), 7.11-7.31 (m, 6H), 7.26-7.49 (m, 2H), 9.40- 9.46 (m,1H), 9.56 (s, 1H). LCMS (Method A): 1.157 min, MS: ES⁺ 391.1 (M + 1)Using Intermediate 22 and 1,2,3,4- tetrahydro-2,7-naphthyridineaccording to Method 1. Note: Duplication of peaks observed in the ¹HNMR-material is a mixture of rotamers. 43 (2-benzyloxy- 4,6-dihydroxy-3-methyl-phenyl)- (3,4-dihydro-1H- 2,6- naphthyridin-2- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.92-1.96 (d, 3H), 2.74-2.75 (m, 2H),3.41-3.47 (m, 1H), 3.73-4.00 (m, 1H), 4.43-4.84 (m, 4H), 6.26- 6.29 (m,1H), 7.10-7.31 (m, 6H), 8.27-8.37 (m, 2H), 9.40-9.45 (d, 1H), 9.55(s,1H). LCMS (Method A): 1.193 min, MS: ES⁺ 391.2 (M + 1) UsingIntermediate 22 and 1,2,3,4- tetrahydro-2,6-naphthyridine according toMethod 1. Note: Duplication of peaks observed in the ¹H NMR-material isa mixture of rotamers. 44 3,4-dihydro-1H- isoquinolin-2-yl-[4,6-dihydroxy- 3-methyl-2-(m- tolylmethoxy) phenyl]methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.93-1.96 (d, 3H), 2.12-2.16 (m, 3H),2.75-2.84 (m, 2H), 3.42-3.45 (m, 1H), 3.62-4.04 (m, 1H), 4.41- 4.85 (m,4H), 6.27-6.28 (m, 1H), 7.01-7.27 (m, 8H), 9.39-9.41 (d, 1H), 9.52(s,1H). LCMS (Method A): 2.150 min, MS: ES⁺ 404.3 (M + 1) UsingIntermediate 33 and 1,2,3,4- tetrahydroisoquinoline according toMethod 1. Note: Duplication of peaks observed in the ¹H NMR-material isa mixture of rotamers. 45 3,4-dihydro-1H- isoquinolin-2-yl-[4,6-dihydroxy- 3-methyl-2-(2- pyridylmethoxy) phenyl]methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.93-1.96 (d, 3H), 2.67-2.75 (m, 2H),3.43-3.48 (m, 1H), 3.62-3.92 (m, 1H), 4.43 (s, 1H), 4.71-4.95 (m, 3H),6.29 (s, 1H), 7.04-7.31 (m, 6H), 7.51-7.74 (m, 1H), 8.45 (s, 1H), 9.40-9.44 (d, 1H), 9.55 (s, 1H). LCMS (Method A): 1.362 min, MS: ES⁺ 391.2(M + 1). Using Intermediate 34 and 1,2,3,4- tetrahydroisoquinolineaccording to Method 1. Note: Duplication of peaks observed in the ¹HNMR-material is a mixture of rotamers. 46 [4,6-dihydroxy- 3-methyl-2-(2-pyridylmethoxy) phenyl]-(7- methoxy-3,4- dihydro-1H- isoquinolin-2-yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.93-1.95 (d, 3H), 2.67 (s, 2H), 3.42- 3.44(m, 1H), 3.55-3.91 (m, 4H), 4.41 (s, 1H), 4.68-4.95 (m, 3H), 6.29 (s,1H), 6.64-6.82 (m, 2H), 7.01- 7.03 (d, J = 8.0 Hz, 1H), 7.24-7.32 (m,2H), 7.54-7.77 (m, 1H), 8.46 (s, 1H), 9.41-9.44 (d, 1H), 9.56 (s, 1H).LCMS (Method A): 1.381 min, MS: ES⁺ 421.2 (M + 1) Using Intermediate 34and 7- methoxy-1,2,3,4- tetrahydroisoquinoline according to Method 1.Note: Duplication of peaks observed in the ¹H NMR-material is a mixtureof rotamers. 47 [4,6-dihydroxy- 3-methyl-2-(2- pyridylmethoxy)phenyl]-(6- methoxy-3,4- dihydro-1H- isoquinolin-2- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.92-1.96 (d, 3H), 2.68-2.72 (m, 2H),3.37-3.44 (m, 1H), 3.58-3.91 (m, 4H), 4.35 (s, 1H), 4.63-4.95 (m, 3H),6.27-6.29 (m, 1H), 6.69 (s, 1H), 6.78-6.95 (m, 1H), 7.12-7.31 (m, 2H),7.54-7.73 (m, 1H), 8.46 (s, 1H), 9.39-9.44 (m, 1H), 9.55 (s, 1H). LCMS(Method A): 1.329 min, MS: ES⁺ 421.1 (M + 1) Using Intermediate 34 and6- methoxy-1,2,3,4- tetrahydroisoquinoline according to Method 1. Note:Duplication of peaks observed in the ¹H NMR-material is a mixture ofrotamers. 48 3,4-dihydro-1H- isoquinolin-2-yl- [2-[(4- fluorophenyl)methoxy]-4,6- dihydroxy-3- methyl- phenyl]methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.92-1.95 (d, 3H), 2.74-2.75 (m, 2H),3.38-3.48 (m, 1H), 3.63-4.00 (m, 1H), 4.40-4.82 (m, 4H), 6.27- 6.28 (d,1H), 6.96-7.02 (m, 2H), 7.09- 7.19 (m, 3H), 7.21-7.27 (m, 3H), 9.40-9.42(d, 1H), 9.53 (s,1H). LCMS (Method A): 2.008 min, MS: ES⁺ 408.2 (M + 1)Using Intermediate 32 and 1,2,3,4- tetrahydroisoquinoline according toMethod 1. Note: Duplication of peaks observed in the ¹H NMR-material isa mixture of rotamers. 49 (2-(benzyloxy)- 4,6- dihydroxyphenyl) (5-((4-methylpiperazin- 1-yl)methyl) isoindolin-2- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.23 (s, 3H), 2.70-2.77 (m, 4H), 3.29- 3.59(m, 4H), 4.50 (s, 2H), 4.75 (s, 2H), 5.04 (s, 2H), 6.03 (d, J = 11.6 Hz,2H), 7.23-7.32 (m, 6H), 7.45-7.50 (m, 3H), 9.56-9.65 (m, 2H), 11.67(brs, 2H). LCMS (Method E): 1.101 min, MS: ES+ 474.2 (M + 1) UsingIntermediate 21 and 2,3- dihydro-5-[(4-methyl-1-piperazinyl)methyl]-1H-isoindole according to Method 1 50 (4-aminoisoindolin- 2-yl)(2- (benzyloxy)-4,6- dihydroxy-3- methylphenyl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.97 (s, 3H), 4.30-4.63 (m, 3H), 4.67- 4.72(m, 2H), 4.90-4.93 (m, 1H), 5.58 (brs, 2H), 6.31 (d, J = 4.4 Hz, 1H),6.43-6.60 (m, 2H), 6.96-7.00 (m, 1H), 7.30-7.36 (m, 5H), 9.48- 9.53 (m,2H). LCMS (Method E): 1.750 min, MS: ES+ 391.3 (M + 1). UsingIntermediate 22 and isoindolin- 4-amine according to Method 1 Note:Duplication of peaks observed in the ¹H NMR-material is a mixture ofrotamers 51 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(4-vinylisoindolin- 2-yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.90 (d, J = 6.8 Hz, 3H), 4.44-4.66 (m,2H), 4.72-4.91 (m, 4H), 5.27- 5.41 (dd, J = 10.8, 11.6 Hz, 1H), ),5.64-5.80 (dd, J = 17.6, 17.6 Hz, 1H), 6.31 (s, 1H), 6.52-6.59 (m, 1H),6.75-6.82 (m, 1H), 7.24-7.36 (m, 6H), 7.39-7.52 (m, 2H), 9.51-9.58 (s,1H). LCMS (Method A): 2.127 min, MS: ES+ 402.2 (M + 1) UsingIntermediate 22 and 4- vinylisoindoline according to Method 1. Note:Duplication of peaks observed in the ¹H NMR-material is a mixture ofrotamers 52 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(7-methoxy-3,4- dihydroisoquinolin- 2(1H)- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.94 (d, J = 9.2 Hz, 3H), 2.68 (d, J = 6.4Hz, 2H), 3.65 (s, 3H), 4.40 (s, 1H), 4.57-4.69 (m, 1H), 4.74-4.86 (m,1H), 6.27 (s, 1H), 6.63-6.76 (m, 2H), 6.68 (s, 1H), 7.00-7.05 (m, 1H),7.22- 7.31 (m, 5H), 9.40 (s, 1H), 9.51 (d, J = 4.8 Hz, 1H). LCMS (MethodA): 1.951 min, MS: ES+ 420.22 (M + 1) Using Intermediate 22 and 7-methoxy-1,2,3,4- tetrahydroisoquinoline according to Method 1. Note:Duplication of peaks observed in the ¹H NMR-material is a mixture ofrotamers 53 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(5,8-dihydro-1,7- naphthyridin- 7(6H)- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.94 (d, J = 17.6 Hz, 3H), 2.76 (s, 2H),3.46-3.50 (m, 2H), 4.36-4.43 (m, 1H), 4.57-4.59 (m, 1H), 4.68-4.71 (m,1H), 4.77-4.84 (m, 1H), 6.29 (d, J = 8.4 Hz, 1H), 7.16-7.31 (m, 6H),7.51-7.56 (m, 1H), 8.30-8.43 (m, 1H), 9.45 (d, J = 11.6 Hz, 1H), 9.57(d, J = 3.6 Hz, 1H). LCMS (Method A): 1.366 min, MS: ES+ 391.22 (M + 1)Using Intermediate 22 and 5,6,7,8- tetrahydro-1,7-naphthyridineaccording to Method 1. Note: Duplication of peaks observed in the ¹HNMR-material is a mixture of rotamers 54 (2-(benzyloxy)-4,6-dihydroxy-3- methylphenyl)(7,8- dihydro-1,6- naphthyridin- 6(5H)-yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.95 (d, J = 17.6 Hz, 3H), 2.83-2.84 (m,2H), 3.48-3.55 (m, 2H), 4.46- 4.50 (m, 1H), 4.57-4.60 (m, 1H), 4.68-4.70(m, 1H), 4.77-4.85 (m, 1H), 6.28 (d, J = 12.4 Hz, 1H), 7.20- 7.29 (m,5H), 7.48-7.50 (m, 1H), 7.69-7.71 (m, 1H), 8.35-8.36 (m, 1H), 9.46 (s,1H), 9.55 (s, 1H). LCMS (Method E): 1.098 min, MS: ES+ 391.27 (M + 1)Using Intermediate 22 and 5,6,7,8- tetrahydro-1,6-naphthyridineaccording to Method 1. Note: Duplication of peaks observed in the ¹HNMR-material is a mixture of rotamers 55 (2-(benzyloxy)-4,6-dihydroxy-3- methylphenyl)(7,8- dihydropyrido[4,3- d]pyrimidin-6(5H)- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.95 (d, J = 18.4 Hz, 3H), 2.78-2.88 (m,2H), 3.48-3.55 (m, 2H), 4.68- 4.92 (m, 4H), 6.28 (d, J = 13.6 Hz, 1H),7.16-7.31 (m, 5H), 8.72 (s, 1H), 8.92 (d, J = 10.4 Hz, 1H), 9.50 (s,1H), 9.59 (s, 1H). LCMS (Method A): 1.378 min, MS: ES+ 392.12 (M + 1)Using Intermediate 22 and 5,6,7,8- tetrahydropyrido[4,3-d]pyrimidineaccording to Method 1. Note: Duplication of peaks observed in the ¹HNMR-material is a mixture of rotamers 56 (2-(benzyloxy)-4,6-dihydroxy-3- methylphenyl)(5,8- dihydropyrido[3,4- d]pyrimidin-7(6H)- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.95 (d, J = 20 Hz, 3H), 2.67-2.83 (m, 2H),3.43-3.49 (m, 2H), 4.33- 4.46 (m, 1H), 4.60-4.86 (m, 3H), 6.28 (d, J =14.8 Hz, 1H), 7.14-7.24 (m, 3H), 7.30-7.32 (m, 2H), 8.54 (d, J = 6.8 Hz,1H), 8.90-9.00 (m, 1H), 9.44-9.50 (m, 1H), 9.60 (d, J = 6.8 Hz, 1H).LCMS (Method E): 1.414 min, MS: ES+ 392.20 (M + 1) Using Intermediate 22and 5,6,7,8- tetrahydropyrido[3,4-d]pyrimidine according to Method 1.Note: Duplication of peaks observed in the ¹H NMR-material is a mixtureof rotamers 57 (3,4- dihydroisoquinolin- 2(1H)-yl)(4,6- dihydroxy-3-methyl-2-((1- methyl-1H- pyrazol-3- yl)methoxy)phenyl) methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.92 (d, J = 10 Hz, 3H), 2.68-2.82 (m, 2H),3.75 (d, J = 11.6 Hz, 5H), 4.39- 4.41 (m, 1H), 4.52-4.62 (m, 1H),4.68-4.84 (m, 1H), 6.06-6.11 (m, 1H), 6.25 (d, J = 6.8 Hz, 1H), 7.00-7.02 (m, 3H), 7.10-7.26 (m, 2H), 7.52-7.58 (m, 1H), 9.37 (d, J = 11.6Hz, 1H), 9.50 (s, 1H). LCMS (Method A): 1.534 min, MS: ES+ 394.20(M + 1) Using Intermediate 35 and 1,2,3,4- tetrahydroisoquinolineaccording to Method 1. Note: Duplication of peaks observed in the ¹HNMR-material is a mixture of rotamers 58 (2-(benzyloxy)- 4,6-dihydroxyphenyl) (3,4- dihydroisoquinolin- 2(1H)- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 2.67-2.75 (m, 2H), 3.44-3.56 (m, 2H),4.74-5.00 (m, 4H), 5.95-5.99 (m, 2H), 7.03-7.23 (m, 9H), 9.48- 9.50 (m,2H). LCMS (Method A): 1.900 min, MS: ES+ 376.20 (M + 1) UsingIntermediate 21 and 1,2,3,4- tetrahydroisoquinoline according toMethod 1. Note: Duplication of peaks observed in the ¹H NMR-material isa mixture of rotamers 59 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(isoindolin-2- yl)methanone

¹H NMR (DMSO-d6, 400 MHz): δ 1.97 (s, 3H), 4.43-4.58 (m, 2H), 4.71- 4.76(m, 3H), 4.90-4.92 (m, 1H), 6.30 (s, 1H), 7.24-7.38 (m, 9H), 9.51 (s,1H), 9.56 (s, 1H). LCMS (Method E): 1.911 min, MS: ES+ 376.22 (M + 1)Using Intermediate 22 and isoindoline according to Method 1. 60(2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(7- ((dimethylamino)methyl)-3,4- dihydroisoquinolin- 2(1H)- yl)methanone

¹H NMR (DMSO-d6, 400 MHz, D₂O exchange); Material is a mixture ofrotamers: δ ppm 1.87 and 1.93 (singlets, 3H), 2.26 (3, 3H), 2.38 (s,3H), 2.68-2.79 (m, 3H), 3.35-3.44 (m, 2H), 3.44-3.54 (m, 1H), 3.62 (bs,1H), 3.75 (bs, 1H), 3.98-4.02 (m, 1H), 4.33-4.38 (m, 1H), 4.51-4.80 (m,3H), 6.21 (s, br, 1H), 7.10-7.25 (m, 7H), 7.49-7.51 (m, 1H). LCMS(Method A): 1.220 min, MS ES+ 447.2 (M + 1). Prepared using Intermediate22 and Intermediate 42 according to Method 1. 61 (2-(benzyloxy)-4,6-dihydroxy-3- methylphenyl)(6- ((dimethylamino) methyl)-3,4-dihydroisoquinolin- 2(1H)- yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz, 335.1 K); Material is amixture of rotamers: δ 1.97 (s, 3H), 2.30 (s, 6H), 2.77-2.79 (m, 2H),3.45- 3.46 (m, 2H), 3.49-3.51 (m, 2H), 3.53-3.58 (m, 2H), 4.74 (s, br,2H), 6.28 (s, 1H), 7.09-7.25 (m, 8H), 9.15 (s, 1H, D₂O exchangeable),9.28 (s, 1H, D₂O exchangeable). LCMS (Method A): 1.151 min, MS: ES+447.3 (M + 1). Prepared using Intermediate 22 and Intermediate 43according to Method 1. 62 (S)-(2- (Benzyloxy)-4,6- dihydroxy-3-methylphenyl)(3- (hydroxymethyl)- 3,4- dihydroisoquinolin- 2(1H)-yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz, 335 K); Material is amixture of rotamers: δ 1.97 and 1.98 (singlets, 3H), 2.84-2.97 (m, 2H),3.25-3.26 (m, 1H), 3.47-3.53 (m, 1H), 3.90-3.92 (m, 1H), 4.17-4.29 (m,1H), 4.40-4.41 (m, 1H), 4.54- 5.03 (m, 3H), 5.22-5.27 (m, 1H), 6.23-6.30(m, 1H), 7.01-7.33 (m, 6H), 7.38-7.43 (m, 2H), 9.03-9.19 (m, 1H, D₂Oexchangeable), 9.27 (m, 1H, D₂O exchangeable). LCMS (Method A): 1.829min, MS: ES+ 420.3 (M + 1). Prepared using Intermediate 22 and(S)-(1,2,3,4-tetrahydroisoquinolin-3- yl)methanol according to Method 1.63 (2-(benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(1- (hydroxymethyl)isoindolin-2- yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz, 335 K); Material is amixture of rotamers: δ 1.99 (2 singlets, 3H), 3.53-3.59 (m, 1H),3.96-3.97 (m, 1H), 4.55-4.99 (m, 5H), 5.26-5.28 (m, 1H), 6.30 (s, br,1H), 7.08 (s, 1H), 7.26-7.45 (m, 8H), 9.24 (s, 1H, D₂O exchangeable),9.32 (s, 1H, D₂O exchangeable). LCMS (Method A): 1.800 min, MS: ES+406.27 (M + 1). Prepared using Intermediate 22 and(isoindolin-1-ylmethanol hydrochloride according to Method 1. 64 (R)-(2-(benzyloxy)-4,6- dihydroxy-3- methylphenyl)(3- (hydroxymethyl)-3,4-dihydroisoquinolin- 2(1H)-yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz, 335 K); Material is amixture of rotamers: δ 1.95-1.97 (2 singlets, 3H), 2.83-2.88 (m, 1H),2.92-2.02 (m, 1H), 3.25-3.31 (m, 1H), 3.45-3.46 (m, 1H), 4.17-5.26 (m,5H), 6.23-6.29 (m, 1H), 7.01- 7.21 (m, 7H), 7.29-7.43 (m, 2H), 9.01-9.26(m, 2H, D₂O exchangeable). LCMS (Method A): 1.805 min, MS ES+: 420.17(M + 1). Prepared using Intermediate 22 and(R)-(1,2,3,4-tetrahydroisoquinolin-3- yl)methanol according to Method 1.65 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(1-(hydroxymethyl)-3,4- dihydroisoquinolin- 2(1H)-yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz, 340 K); material is amixture of rotamers: δ 1.88-1.96 (m, 3H), 2.68-2.72 (m, 1H), 2.94-3.00(m, 1H), 3.54-3.56 (m, 1H), 3.70- 3.71 (m, 1H), 3.82-3.83 (m, 1H),4.56-4.57 (m, 1H), 4.65-4.66 (m, 1H), 4.81-4.84 (m, 1H), 5.06-5.09 (m,1H), 5.54-5.61 (m, 1H), 6.27 and 6.30 (2 singlets, 1H), 6.93-7.17 (m,6H), 7.31-7.40 (m, 2H), 7.48 (m, 1H), 9.10 (bs, 2H, D₂O exchangeable).LCMS (Method A): 1.715 min, MS: ES+ 420.20 (M + 1). Prepared usingIntermediate 22 and Intermediate 44 according to Method 1. 66(2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(4- (hydroxymethyl)-3,4-dihydroisoquinolin- 2(1H)-yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz, 340 K); material is amixture of rotamers: δ 1.95 and 1.98 (singlets, 3H), 2.90-2.92 (m, 1H),3.47-3.60 (m, 4H), 4.35-4.36 (m, 2H), 4.76-4.78 (m, 2H), 6.26 and 6.29(singlets, 1H), 7.17-7.30 (m, 9H), 9.09-9.23 (m, 2H, D₂O exchangeable).LCMS (Method A): 1.809 min, MS ES+: 420.27 (M + 1). Prepared usingIntermediate 22 and Intermediate 45 according to Method 1. 67(2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(2,3- dihydro-4H-benzo[b][1,4] oxazin-4- yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz); material is a mixture ofrotamers: δ 1.97 (s, 3H), 3.64 (m, 1H), 3.88 (m, br, 1H), 4.18-4.20 (m,2H), 4.86 (m, 2H), 6.25 (s, 1H), 6.75- 6.87 (m, 2H), 6.99 (m, 2H), 7.30-7.38 (m, 5H), 9.37 (s, 2H, D₂O exchangeable). LCMS (Method A): 2.060min, MS ES+ 392.22 (M + 1). Prepared using Intermediate 22 and3,4-dihydro-2H-benzo[b][1,4]oxazine according to Method 2. 68(2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(5- ((dimethylamino)methyl)isoindolin- 2-yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz); material is a mixture ofrotamers: δ 1.99 (s, 3H), 2.13 (s, 3H), 2.16 (s, 3H), 3.36-3.39 (m, 2H),4.50- 4.51 (m, 2H), 4.73-4.74 (m, 2H), 4.90-4.91 (m, 2H), 6.31 (s, 1H),7.17- 7.36 (m, 8H), 8.45 (s, br, 1H), 9.32 (s, br, 2H, D₂Oexchangeable). LCMS (Method A): 1.160 min, MS: ES+ 433.27 (M + 1). UsingIntermediate 22 and Intermediate 46 according to Method 1. 69(2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(5- (morpholinomethyl)isoindolin-2- yl)methanone

¹H NMR (DMSO-d6, 400 MHz); material is a mixture of rotamers: δ 1.97 (s,3H), 2.33 (bs, 4H), 3.43-3.46 (m, 2H), 3.54-3.56 (m, 4H), 4.41- 4.43 (m,2H), 4.72-4.92 (m, 4H), 6.31 (s, 1H), 7.17-7.36 (m, 8H), 9.51 (s, 1H,D₂O exchangeable). 9.55 (s, 1H, D₂O exchangeable). LCMS (Method A):1.286 min, MS ES+: 475.17 (M + 1). Prepared using Intermediate 22 andIntermediate 47 according to Method 1. 70 (2-(Benzyloxy)-4,6-dihydroxy-3- methylphenyl) (indolin-1- yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz, 350 K); material is amixture of rotamers: δ 1.98 (s, 3H), 3.01-3.03 (m, 1H), 3.46-3.54 (m,1H), 3.90-3.91 (m, 2H), 4.83-5.00 (m, 2H), 6.33 (s, 1H), 6.90-6.99 (m,4H), 7.20-7.33 (m, 5H), 9.38 (s, br, 2H, D₂O exchangeable). LCMS (MethodA): 2.003 min, MS ES+ 376.22 (M + 1). Prepared using Intermediate 22 andindoline according to Method 1. 71 (2-(Benzyloxy)-4,6- dihydroxyphenyl)(indolin-1- yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz, 330 K); material is amixture of rotamers: δ 2.99-3.05 (m, 2H), 3.80-3.82 (m, br, 2H), 5.00-5.03 (m, br, 2H), 6.04 (s, 2H), 7.16 7.27 (m, 8H), 8.15-8.17 (m, br 1H),9.38-9.44 (m, 2H, D₂O exchangeable). LCMS (Method A): 1.921 min, MS ES+362.2 (M + 1). Prepared using Intermediate 21 and indoline according toMethod 1. 72 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl) (3,4-dihydroquinolin- 1(2H)- yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz, 335 K); material is amixture of rotamers: δ 1.84-1.90 (m, 2H), 1.94 (s, 3H), 2.65-2.67 (m,2H), 3.53-3.69 (m, 2H), 4.84-4.85 (m, 2H), 6.20 (s, 1H), 6.95-6.97 (m,2H), 7.09-7.10 (m, 1H), 7.30-7.39 (m, 6H), 9.90-9.24 (m, 2H, D₂Oexchangeable). LCMS (Method A): 2.222 min, MS ES+ 390.22 (M + 1).Prepared using Intermediate 22 and 1,2,3,4-tetrahydroquinoline accordingto Method 1. 73 (2-(Benzyloxy)- 4,6- dihydroxyphenyl) (3,4-dihydroquinolin- 1(2H)- yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz, 335 K); material is amixture of rotamers: δ 1.80-1.85 (m, 2H), 2.63-2.67 (m, 1H), 3.46-3.53(m, 2H), 3.75-3.76 (m, 1H), 4.77- 4.95 (m, 2H), 5.87 (s, 1H) 5.94 (s,1H), 6.90-6.99 (m, 2H), 7.07-7.09 (m, 1H), 7.25-7.34 (m, 6H), 9.25- 9.32(m, 2H, D₂O exchangeable). LCMS (Method A): 1.976 min, MS ES+ 376.30(M + 1). Prepared using Intermediate 21 and 1,2,3,4-tetrahydroquinolineaccording to Method 1. 74 (2-(Benzyloxy)- 4,6-dihydroxy-3-methylphenyl)(1,3- dihydro-2H- pyrrolo[3,4- c]pyridin-2- yl)methanone

¹H NMR (DMSO-d6, 400 MHz); material is a mixture of rotamers: δ 1.97 (s,3H), 4.48-4.59 (m, 2H), 4.72- 4.93 (m, 4H), 6.31 (s, 1H), 7.24- 7.35 (m,4H), 7.43-7.44 (m, 1H), 8.44-8.48 (m, 2H), 8.61 (s, 1H), 9.58- 9.61 (m,2H, D₂O exchangeable). LCMS (Method A): 1.103 min, MS ES+ 377.3 (M + 1).Prepared using Intermediate 22 and 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine.2HCl according to Method 1. 75 (2-(Benzyloxy)-4,6-dihydroxy-3- methylphenyl)(4- ((4- methylpiperazin-1-yl)methyl)isoindolin- 2-yl)methanone

High temperature ¹H NMR (DMSO- d6, 400 MHz, 340 K); material is amixture of rotamers: δ 2.00 (s, 3H), 2.10-2.40 (m, 12H), 4.41-4.63 (m,2H), 4.74-4.93 (m, 4H), 6.32 (s, 1H), 7.17-7.34 (m, 8H), 9.17 (bs, 2H,D₂O exchangeable). LCMS (Method A): 1.467 min, MS ES+: 488.22 (M + 1).Prepared using Intermediate 22 and Intermediate 48 according toMethod 1. 76 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(4-(morpholinomethyl) isoindolin-2- yl)methanone

¹H NMR (DMSO-d6, 400 MHz); material is a mixture of rotamers: δ 1.97 and1.98 (singlets, 3H), 2.19 (s, 2H), 2.35 (s, 2H), 3.34 (s, 1H), 3.40-3.49 (m, 3H), 3.57 (s, br, 2H), 4.44- 4.45 (m, 1H), 4.54-4.56 (m, 1H),4.67-4.73 (m, 2H), 4.79-4.80 (m, 1H), 4.90-4.93 (m, 1H), 6.30 and 6.31(singlets, 1H), 7.13-7.21 (m, 2H), 7.26-7.27 (m, 4H), 7.32-7.36 (m, 2H),9.48-9.50 (m, 1H, D₂O exchangeable), 9.54 (s, 1H, D₂O exchangeable).LCMS (Method A): 1.326 min, MS ES+ 475.2 (M + 1). Prepared usingIntermediate 22 and Intermediate 49 according to Method 1. 77 2-(2-(Benzyloxy)-4,6- dihydroxy-3- methylbenzoyl)- N,N-dimethyl- 1,2,3,4-tetrahydroisoquinoline- 7-carboxamide

High temperature ¹H NMR (DMSO- d6, 400 MHz, 330 K); material is amixture of rotamers: δ 1.96 (s, 3H), 2.97 (s, br, 6H), 3.50-3.52 (m,2H), 3.71-4.00 (m, 2H), 4.74-4.88 (m, 4H), 6.28 (s, 1H), 7.17-7.24 (m,8H), 9.20 (s, 1H, D₂O exchangeable), 9.32 (s, 1H, D₂O exchangeable).LCMS (Method A): 1.744 min, MS ES+ 461.2 (M + 1). Prepared usingIntermediate 22 and N, N-dimethyl-1, 2,3,4- tetrahydroisoquinoline-7-carboxamide (Intermediate 42a) according to Method 1. 78 2-(2-(benzyloxy)-4,6- dihydroxy-3- methylbenzoyl)- N,N-dimethyl- 1,2,3,4-tetrahydroisoquinoline- 6-carboxamide

High temperature ¹H NMR (DMSO- d6, 400 MHz, 335 K); material is amixture of rotamers: δ 1.97 (s, 3H), 2.78-2.81 (m, 2H), 2.93-2.94 (s,br, 6H), 3.67-3.69 (m, 1H), 3.96-3.97 (m, 1H), 4.45-4.47 (m, 1H), 4.75-4.76 (m, 3H), 6.28 (s, 1H), 7.15-7.25 (m, 8H), 9.17 (s, 1H, D₂Oexchangeable), 9.29 (s, 1H, D₂O exchangeable). LCMS (Method A): 1.648min, MS ES+ 461.27 (M + 1). Prepared using Intermediate 22 and N,N-dimethyl-1,2,3,4- tetrahydroisoquinoline-6- carboxamide (Intermediate43a) according to Method 1. 79 (2-(Benzyloxy)- 4,6-dihydroxy-3-methylphenyl)(4- ((tetrahydrofuran-3- yl)amino)isoindolin-2-yl)methanone

¹H NMR (DMSO-d6, 400 MHz); material is a mixture of rotamers: δ1.75-1.76 (m, 1H), 1.98 (s, 3H), 2.07- 2.33 (m, 1H), 3.50-3.55 (m, 2H),3.60-3.69 (m, 2H), 4.32-4.35 (m, 2H), 4.59-4.63 (m, 1H), 4.67-4.74 (m,2H), 4.90-4.92 (m, 1H), 5.33- 5.48 (m, 1H), 6.30 and 6.31 (singlets,1H), 6.41 (m, 1H), 6.60-6.61 (m, 1H), 7.03-7.11 (m, 1H), 7.27-7.36 (m,5H), 9.46-9.56 (m, 2H, D₂O exchangeable). LCMS (Method A): 1.943 min, MSES+ 461.2 (M + 1). Prepared using Intermediate 22 and Intermediate 50according to Method 1. 80 (2-(Benzyloxy)- 4,6-dihydroxy-3-methylphenyl)(4- (oxetan-3- ylamino)isoindolin- 2-yl)methanone

¹H NMR (DMSO-d6, 400 MHz); material is a mixture of rotamers: δ 1.98 and1.99 (singlets, 3H), 4.35- 4.53 (m, 5H), 4.55-4.60 (m, 1H), 4.68-4.77(m, 2H), 4.83-4.86 (m, 2H), 5.93-6.18 (m, 1H), 6.31 and 6.32 (singlets,1H), 6.50-6.64 (m, 1H), 7.00-7.08 (m, 1H), 7.28-7.38 (m, 5H), 9.48-9.54(m, 2H, D₂O exchangeable). LCMS (Method A): 1.853 min, MS ES+ 447.20(M + 1). Prepared using Intermediate 22 with Intermediate 51 accordingto Method 1. 81 (2-(Benzyloxy)- 4,6-dihydroxy-3- methylphenyl)(4-(3-hydroxypiperidin- 1-yl)isoindolin- 2-yl)methanone

¹H NMR (DMSO-d6, 400 MHz); material is a mixture of rotamers: δ1.27-1.40 (m, 1H), 1.57-1.60 (m, 2H), 1.82 (m, 1H), 1.96 and 1.99(singlets, 3H), 2.92 (m, 1H), 3.25- 3.28 (m, 1H), 3.64 (m, br, 1H),4.45- 4.52 (m, 3H), 4.65-4.75 (m, 3H), 4.86-4.93 (m, 2H), 6.30 (m, 1H),6.83-7.01 (m, 2H), 7.19-7.36 (m, 6H), 9.19-9.23 (m, 1H, D₂Oexchangeable), 9.30 (s, 1H, D₂O exchangeable). LCMS (Method A): 1.905min, MS ES+ 475.2 (M + 1). Prepared using Intermediate 22 andIntermediate 52 according to Method 1.

Example 82:2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile(Reaction Scheme Shown in FIG. 1) 4-Bromoisoindoline hydrochloride

To a stirred solution of tert-butyl 4-bromo-isoindoline-2-carboxylate(0.5 g, 1.67 mmol, 1.0 eq.) in 0CM at 000 (5 mL) was added dropwise 4NHCl in dioxane (5 mL) and the reaction stirred at room temperature for 2h. Reaction completion was monitored by TLC (9:1; 0CM: methanol). Theresulting reaction mixture was concentrated under reduced pressure andthe crude material (0.48 g) was purified by trituration using n-pentane(3×25 mL) to give the title compound (0.47 g, 2.00 mmol, Yield: 100%).

¹H NMR (DMSO-d6, D₂O-exchange 400 MHz): δ 4.48 (s, 2H), 4.62 (s, 2H),7.34 (t, J=7.6, 15.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.59 (d, J=7.6 Hz,1H), 10.06 (s, 2H). LCMS (Method A): 0.766 min, MS: ES+198.03 (M+1).

5-(benzyloxy)-4-(4-bromoisoindoline-2-carbonyl)-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate)

Intermediate 22 (0.5 g, 0.86 mmol, 1.0 eq.) in DMF (5 mL) at 0° C. undernitrogen atmosphere was treated with HATU (0.48 g, 1.28 mmol, 1.5 eq.)and DIPEA (0.22 g, 1.71 mmol, 2.0 eq.) and stirred for 15 min.4-Bromoisoindoline hydrochloride (0.17 g, 0.86 mmol, 1.0 eq.) was addedand the resulting reaction mixture stirred at 0° C. for 1 h. Reactioncompletion was monitored by TLC (ethyl acetate: hexane 1:1). Thereaction mixture was poured into water (50 mL) and extracted with ethylacetate (4×50 mL). The combined organic layer was dried over sodiumsulphate, filtered and concentrated under reduced pressure. The obtainedcrude material (0.6 g) was purified by flash chromatography (product waseluted in 2% methanol in DCM) yielding the title compound (0.45 g, 0.591mmol, Yield: 69%).

LCMS (Method A): 2.860 min, MS: ES+764 (M+1).

((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-bromoisoindolin-2-yl)methanone

To a stirred solution5-(benzyloxy)-4-(4-bromoisoindoline-2-carbonyl)-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (0.1 g, 0.13 mmol, 1.0 eq.) in EtOH: water(2 mL, 1:1) was added aqueous KOH (0.29 g, 0.52 mmol, 40 eq. in minimumwater) at room temperature. The resulting reaction mixture was heated to60° C. and stirred for 2 h. Reaction completion was monitored on TLC(DCM: Methanol 9:1). The resulting reaction mixture was allowed to coolto room temperature, diluted with water (10 mL), neutralized withdiluted HCl and extracted with ethyl acetate (4×20 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude material was purified by flashchromatography (product eluted by 6% methanol in DCM) to give the titlecompound (0.030 g, 0.066 mmol, Yield: 50%).

¹H NMR (DMSO-d6, 400 MHz): 1.98 (2 singlets, 3H), 4.27-4.57 (m, 2H),4.63-4.75 (m, 2H), 4.84-4.95 (m, 2H), 6.30 (d, J=2.4 Hz, 1H), 7.22-7.41(m, 7H), 7.47-7.52 (m, 1H), 9.52-9.60 (m, 2H). LCMS (Method A): 2.379min, MS: ES+456.4 (M+1).

2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile

(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-bromoisoindolin-2-yl)methanone(0.2 g, 0.44 mmol, 1.0 eq) in DMF (2 mL) at room temperature was treatedwith zinc cyanide (0.027 g, 0.23 mmol, 0.54 eq), zinc powder (0.005 g,0.088 mmol, 0.2 eq) and BINAP (0.002 g, 0.044 mmol, 0.1 eq). Thereaction mixture was degassed (N₂ gas) for 10-15 mins. Pd(OAc)₂ (0.002mg, 0.044 mmol, 0.1 eq) was added and the resulting reaction mixtureheated to 100° C. and stirred for 1 h under microwave irradiation. Theresulting reaction was allowed to cool to room temperature, poured intowater (100 mL) and extracted with ethyl acetate (3×110 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated undervacuum. The crude material was purified by flash chromatography (producteluted in 35% EtOAc in hexane) to give the title compound (0.05 g, 0.12mmol. Yield: 28.38%,).

¹H NMR (DMSO-d6, 400 MHz): δ 1.99 (d, J=8.4 Hz, 3H), 4.48-4.52 (m, 1H),4.62-4.93 (m, 5H), 6.31 (2 singlets, 1H), 7.18-7.28 (m, 5H), 7.45-7.61(m, 1H), 7.73-7.79 (m, 2H), 9.57-9.65 (m, 2H). LCMS (Method A): 1.765min, MS ES+401.2 (M+1).

Example 83:2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide(Reaction scheme shown in FIG. 2) Methyl2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindoline-5-carboxylate

A stirred solution of Intermediate 22 (1.2 g, 2.06 mmol, 1.0 eq) in DMF(12 mL) at 0° C. under a nitrogen atmosphere was treated with HATU (1.17g, 3.09 mmol, 1.5 eq.) and DIPEA (0.53 g, 4.12 mmol, 2.0 eq.) andstirred for 15 min. Methyl isoindoline-5-carboxylate hydrochloride(CAS:127168-93-8) (0.40 g, 0.22 mmol, 1.1 eq.) was added and thereaction mixture stirred for 1 h at 0° C. The reaction mixture wasdiluted with ethyl acetate (120 mL) and washed with cold brine solution(3×100 mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude material was purified byflash chromatography (product eluted by 0.8% methanol in DCM) to givethe title compound (0.95 g, 1.28 mmol, Yield: 62%).

¹H NMR, compound is a mixture of rotamers. (DMSO-d6, 400 MHz): δ 1.87(s, 3H), 2.13 (s, br, 3H), 2.46 (s, br, 3H), 3.75-3.87 (singlets, 3H),4.40-4.79 (m, 4H), 6.88 (s, 1H), 7.19-7.32 (m, 8H), 7.51-7.56 (m, 3H),7.67-7.80 (m, 5H), 7.86-7.93 (m, 1H). LCMS (Method A): 2.969 min, 254nm, MS: ES+742.2 (M+1); 3.014 min, 210 nm, MS: ES+742.2 (M+1).

2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl) isoindoline-5-carboxylicacid (Intermediate 58)

To a stirred solution of methyl2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindoline-5-carboxylate(0.95 g, 1.28 mmol, 1.0 eq.) in EtOH: Water (1: 1) (9.5 mL) at roomtemperature was added an aqueous solution of NaOH (0.51 g, 12.82 mmol,10 eq. in 0.5 mL in water). The resulting reaction mixture was heated to90° C. and stirred for 2 h. The reaction mixture was allowed to cool toroom temperature, poured into water (125 mL) and neutralized withdiluted HCl and extracted with ethyl acetate (4×100 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude material was triturated using n-pentane(3×30 mL) and dried using high vacuum to give the title compound (0.45g, 1.07 mmol, Yield: 84%) which was used in the next step withoutpurification.

LCMS (Method A): 1.555 min, MS: ES+420.20 (M+1).

2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide

To a stirred solution of2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-5-carboxylicacid (0.2 g, 0.47 mmol, 1.0 eq.) and (CH₃)₂NH (2M in THF) (0.52 g, 0.52mmol, 1.1 eq.) in THF (2 mL, 10 v) at 0° C. were added T₃P (50% inEtOAc) (0.22 g, 0.71 mmol, 1.5 eq.) and the reaction mixture stirred for15 mins. TEA (0.096 g, 0.95 mmol, 2.0 eq.) was added and the reactionmixture stirred at 0° C. for 1 h. The resulting reaction mixture waspoured into water (30 mL) and extracted by ethyl acetate (4×30 mL). Thecombined organic layer was dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude material was purified by prep. TLCusing 10% methanol in DCM yielding the title compound (0.03 g, 0.06mmol, Yield: 14%).

¹H NMR (DMSO-d6, 400 MHz), compound is a mixture of rotamers: δ 1.97 (s,3H), 2.87 (d, J=14.4 Hz, 3H), 2.95 (m, 3H), 4.43-4.47 (m, 1H), 4.56-4.59(m, 1H), 4.71-4.81 (m, 3H), 4.91 (d, J=10.8 Hz, 1H), 6.30 (s, 1H),7.22-7.43 (m, 8H), 9.54 (d, J=16.4 Hz, 2H). LCMS (Method A): 1.563 min,MS: ES+447.1 (M+1).

Example 84:2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-5-carboxamide

2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-5-carboxamide

A stirred solution of 2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-5-carboxylic acid (0.1 g, 0.23 mmol, 1.0 eq.) (Intermediate58) and MeNH₂·HCl (0.017 g, 0.26 mmol, 1.1 eq.) in THF (1 mL) at 0° C.under nitrogen atmosphere was treated with T₃P (0.11 g, 0.35 mmol, 1.5eq.) and stirred for 15 min. TEA (0.048 g, 0.47 mmol, 2.0 eq.) was addedto the resulting reaction mixture at 0° C. and stirred for 1 h. Thereaction mixture was poured into water (20 mL) and extracted with ethylacetate (3×20 mL). The combined organic layer was dried over sodiumsulphate, filtered and concentrated under reduced pressure. The crudematerial (0.11 g) was purified by normal phase flash chromatography(silica gel: product eluted in 5.2% methanol in DCM) yielding the titlecompound (0.017 g, 0.039 mmol, Yield: 16%).

¹H NMR (DMSO-d6, 400 MHz), compound is a mixture of rotamers: δ ppm 1.99(s, 3H), 2.76-2.79 (m, 3H), 3.18 (m, 1H) 4.47-4.63 (m, 2H), 4.73-4.84(m, 2H), 4.93 (d, J=10.4 Hz, 2H), 6.32 (s, 1H), 7.26-7.40 (m, 5H),7.68-7.76 (m, 1H), 7.81-7.97 (m, 1H), 8.93-8.46 (m, 1H), 9.53-9.58 (m,2H). LCMS (Method A): 1.515 min, MS: ES+433.2 (M+1).

Example 85:2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide(Reaction scheme shown in FIG. 3) 2-(t-Butyl) 4-methylisoindoline-2,4-dicarboxylate

A stirred solution of t-butyl 4-bromoisoindoline-2-carboxylate (2.0 g,6.73 mmol, 1.0 eq) (CAS: 1035235-27-8) in MeOH: DMF (10:1) (22 mL) in anautoclave at room temperature was treated with PdCl₂(dppf) (0.98 g, 1.28mmol, 1.34 eq), DPPF (0.37 g, 0.673 mmol, 0.1 eq) and TEA (2.0 g, 2.01mmol, 3.0 eq). 22 kg/cm² of CO (gas) was applied to reaction mixturewhich was heated to 110° C. and stirred for 24 h. The reaction mixturewas allowed to cool to room temperature and filtered through a celitebed; water (60 mL) was added to filtrate which was extracted with ethylacetate (3×50 mL). The combined organic layer was dried over Na₂SO₄,filtered and concentrated under vacuum. The crude material was purifiedby flash chromatography (product eluted in 5% ethyl acetate in hexane)yielding the title compound (1.5 g, 5.40 mmol. Yield: 80.6%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.46 (s, 9H), 3.86 (s, 3H), 4.62 (d, J=10.4Hz, 2H), 4.82 (d, J=10.0 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.61 (t, br,1H), 7.87 (d, J=7.2 Hz, 1H). LCMS (Method A): 2.172 min, MS: ES+222.2(M−56).

Methyl isoindoline-4-carboxylate hydrochloride

A stirred solution of 2-(t-butyl) 4-methyl isoindoline-2,4-dicarboxylate(1.5 g, 5.41 mmol, 1.0 eq.) in DCM (15 mL) at room temperature wastreated with 4M HCl in dioxane (7.5 mL) at 0° C. The reaction mixturewas stirred for 1 h and then evaporated under reduced pressure and theresultant solid triturated using n-pentane (15 mL) to give the titlecompound (0.95 g, 5.36 mmol, Yield: 100%).

¹H NMR (DMSO-d6, 400 MHz): δ 3.89 (s, br, 3H), 4.55 (s, br, 2H), 4.75(s, br, 2H), 7.55 (t, J=7.6 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.93 (d,J=7.6 Hz, 1H), 10.0 (s, 2H). LCMS (Method A): 0.638 min, MS: ES+178.2(M+1).

2-(2-(Benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindoline-4-carboxylate

Carried out on 4 parallel batches at 0.5 g scale. A stirred solution ofIntermediate 22 (0.5 g, 0.858 mmol, 1.0 eq) in DMF (2 mL) at 0° C. wastreated with HATU (0.489 g, 1.28 mmol, 1.5 eq) and DIPEA (0.553 g, 4.29mmol, 5.0 eq) and stirred for 10 min. Methyl isoindoline-4-carboxylatehydrochloride (0.201 g, 0.944 mmol, 1.1 eq.) dissolved in DMF (1 mL) wasadded dropwise to reaction mixture at 0-5° C. The resulting reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas poured onto ice-cold water (20 mL) and extracted with ethyl acetate(3×20 mL). The combined organic layer was dried through Na₂SO₄, filteredand concentrated under vacuum. The crude material was purified by flashchromatography (eluting product with 3% MeOH in DCM) yielding the titlecompound (2.0 g, 2.69 mmol Yield: 78.7%,) which was progressed to thenext step without purification.

LCMS (Method A): 2.828 min, MS: ES+742.22.

2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carboxylicacid (Intermediate 59)

To a stirred solution of methyl2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindoline-4-carboxylate(1.0 g, 1.34 mmol, 1.0 eq.) in EtOH: Water (1:1) (10 mL) at roomtemperature was added NaOH (2.15 g, 53.92 mmol, 40 eq.). The reactionmixture was heated to 70° C. and stirred for 16 h. The reaction wascooled to 0-5° C. and acidified using saturated solution of KHSO₄ (pH1-2). The aqueous layer was extracted with ethyl acetate (3×30 mL) andthe combined organic layer dried over Na₂SO₄, filtered and concentratedunder vacuum. The crude material was triturated using n-pentane (5 mL)and diethyl ether (5 mL) to give the title compound as a brown oil (0.5g, 1.19 mmol. Yield: 88.5%).

¹H NMR (DMSO-d6, 400 MHz) compound is a mixture of rotamers: δ 1.98 (s,br, 3H), 4.11-4.13 (m, 2H), 4.46-4.72 (m, 2H), 4.85-5.01 (m, 2H), 6.31(s, 1H), 7.23-7.96 (m, 8H), 9.51-9.59 (m, 2H), 13.02 (s, br, 1H). LCMS(Method A): 1.728 min, MS: ES+420.17 (M+1).

2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide

A stirred solution of2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carboxylicacid (0.250 g, 0.596 mmol, 1.0 eq) (Intermediate 59) in DMF (3 mL) at 0°C. was treated with T₃P (50% in EtOAc) (0.568 mL, 0.894 mmol, 1.5 eq),TEA (0.300 g, 2.98 mmol, 5.0 eq) and stirred for 10 mins. Dimethylaminehydrochloride (0.058 g, 0.715 mmol, 1.2 eq) was added to the reactionmixture at 0-5° C. The resulting reaction mixture was stirred at roomtemperature for 2 h. The reaction mixture was poured with ice-cold water(20 ml) and extracted with ethyl acetate (3×30 mL). The combined organiclayer was dried through Na₂SO₄, filtered and concentrated under vacuum.The crude material was purified by flash chromatography (product elutedin 8% methanol in DCM), followed by prep TLC (5% MeOH: DCM system)yielding the title compound as an off white solid (0.034 g, 0.076 mmol.Yield: 12.8%).

High temperature ¹H NMR (DMSO-d6, 400 MHz, 335 K): compound is a mixtureof rotamers δ 1.99 (s, 3H), 2.92 (singlets, br, 6H), 4.43-4.93 (m, 6H),6.30 (s, 1H), 7.24-7.46 (m, 8H), 9.27-9.33 (m, 2H). LCMS (Method A):1.640 min, MS: ES+447.27 (M+1).

Example 86:2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-4-carboxamide

2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-4-carboxamide

To a stirred solution of2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carboxylicacid (0.250 g, 0.596 mmol, 1.0 eq) (Intermediate 59) in THF (3 ml) at 0°C. were added T₃P (50% in EtOAc) (0.284 g, 0.894 mmol, 1.5 eq) and TEA(0.180 g, 1.78 mmol, 3.0 eq). The resulting reaction was stirred at 0°C. for 10 mins. CH₃NH₂ (1M in THF) (0.22 g, 0.715 mmol, 1.2 eq.) wasadded dropwise into reaction mixture at 0° C. and the resulting reactionmixture stirred at room temperature for 16 h. The reaction mixture waspoured into ice-cold water (20 mL) and extracted in ethyl acetate (3×30mL). The combined organic layer was dried through Na₂SO₄, filtered andconcentrated under vacuum. The crude material was purified by flashchromatography (product eluted using 8% methanol in DCM) followed byprep TLC yielding the title compound (0.017 g, 0.039 mmol. Yield: 6.6%).

High temperature ¹H NMR (DMSO-d6, 400 MHz, 335 K) compound is a mixtureof rotamers: δ1.99 (s, br, 3H), 2.71-2.82 (singlets, br, 3H) 4.54-4.97(m, 6H), 6.31 (s, 1H), 7.26-7.62 (m, br, 8H), 8.44 (s, br, 1H),9.49-9.58 (m, 2H). LCMS (Method A): 1.561 min, MS: ES+433.22 (M+1).

Example 87:N-(2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)acetamide

N-(2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)acetamide

A stirred solution of(4-aminoisoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone(0.06 g, 0.15 mmol, 1 eq.) in AcOH (0.5 mL) at 0° C. was treated withacetic anhydride (0.017 g, 0.17 mmol, 1.1 eq.). The resulting reactionmixture was stirred at room temperature for 30 min. Reaction completionwas monitored by TLC (DCM: MeOH; 9.5:0.5). The reaction mixture wasneutralized with sat. NaHCO₃ solution (PH-6-7) and extracted with ethylacetate (3×50 mL). The combined organic layer was dried over Na₂SO₄,filtered and concentrated under vacuum. The crude material was purifiedby preparative TLC (5% MeOH in DCM) yielding the title compound as awhite solid (0.040 g, 0.092 mmol. Yield: 58.8%).

High temperature ¹H NMR (DMSO-d6, 400 MHz, 348K): compound is a mixtureof rotamers: δ 1.99-2.11 (singlets, broad, 6H), 4.55-4.93 (m, 6H), 6.31(s, 1H), 6.99-7.13 (m, 1H), 7.13 (s, br, 1H), 7.25-7.36 (m, 5H),7.54-7.56 (m, 1H), 9.24-9.38 (m, 3H). LCMS (Method A): 1.616 min, MS:ES+433.2 (M+1).

Example 88:((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone(Reaction scheme shown in FIG. 4) t-Butyl4-bromoisoindoline-2-carboxylate

A stirred solution of 4-bromoisoindoline hydrochloride (CAS:923590-95-8) (15 g, 64.38 mmol, 1.0 eq.) in DCM (150 mL) at roomtemperature was treated with TEA (19.50 g, 128.77 mmol, 2.0 eq.) andstirred for 15 min. Boc anhydride (28.10 g, 128.77 mmol, 2.0 eq.) wasadded and the reaction mixture stirred for 16 h. The resulting reactionmixture was poured into water (250 mL) and extracted with ethyl acetate(4×250 mL). The combined organic layer was dried over Na₂SO₄, filteredand concentrated under reduced pressure; the crude material was purifiedby flash chromatography (product was eluted with 2% ethyl acetate inhexane) yielding (15.4 g, 51.85 mmol, Yield: 81%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.46 (s, 9H), 4.51 (d, J=9.6 Hz, 2H), 4.68(d, J=10.4 Hz, 2H), 7.23-7.27 (m, 1H), 7.33-7.36 (m, 1H), 7.49 (d, J=7.4Hz, 1H).

t-Butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate

8 Reactions at 1 g scale carried out in parallel and product combined. Astirred solution of t-butyl 4-bromoisoindoline-2-carboxylate (1.0 g,33.67 mmol, 1 eq.) in 1.4-dioxane (10 mL) at room temperature wastreated with bis(pinacolato)diborane (1.01 g, 40.06 mmol, 1.19 eq.) andpotassium acetate (0.66 g, 67.34 mmol, 2.0 eq.) and degassed withnitrogen gas for 15 min. PdCl₂(dppf) (0.49 g, 06.73 mmol, 0.2 eq.) wasadded and the resulting reaction mixture heated to 90° C. and stirredfor 16 h. The resulting reaction mixture was allowed to cool to roomtemperature and filtered, the filtrate was concentrated under reducedpressure. The crude material was purified by flash chromatography(product eluted with 7% ethyl acetate in hexane) yielding the titlecompound (9 g, 26.08 mmol, Yield: 97%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.30 (s, 12H), 1.46 (s, 9H), 4.55-4.58 (m,2H), 4.65-4.67 (m, 2H), 7.28-7.31 (m, 1H), 7.45 (d, J=7.2 Hz, 1H), 7.58(d, J=6.4 Hz, 1H). LCMS (Method A): 2.821 min, MS: ES+246.1 (M−100).

t-Butyl 4-hydroxyisoindoline-2-carboxylate

A stirred solution of t-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate(2.3 g, 6.66 mmol, 1.0 eq.) in THF (23 mL) at 0° C. was treated withNaOH (0.53 g, 13.33 mmol, 2.0 eq.) and H₂O₂ solution (0.95 g, 27.99mmol, 4.2 eq.) added dropwise. The resulting reaction mixture wasstirred at 0° C. for 1 h. The resulting reaction mixture was poured intowater (80 mL) and neutralized with dil. HCl and extracted with ethylacetate (3×100 mL). The combined organic layer was dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude materialwas purified by flash chromatography (product eluted by 11% ethylacetate in hexane) yielding the title compound (1.5 g, 6.37 mmol, Yield:96%).

¹H NMR (CDCl₃-400 MHz): δ 1.54 (s, 9H), 4.65-4.70 (m, 3H), 4.81 (s, 1H),6.71-6.85 (m, 2H), 7.14-7.19 (m, 1H). LCMS (Method A): 2.015 min, MS:ES+136.1 (M−100).

Isoindolin-4-ol hydrochloride

A stirred solution of t-butyl 4-hydroxyisoindoline-2-carboxylate (2.8 g,11.91 mmol, 1.0 eq.) in DCM (28 mL) at 0° C. was treated with 4N HCl indioxane (14 mL) added dropwise. The resulting reaction mixture wasstirred for 1 h at room temperature. The resulting reaction mixture wasconcentrated under reduced pressure and the crude material trituratedusing n-pentane (3×50 mL) followed by drying under high vacuum yieldingthe title compound (1.8 g, 13.33 mmol, Yield: 87%).

¹H NMR (DMSO-d6, 400 MHz): δ 4.37 (s, 2H), 4.45 (s, 2H), 6.78-6.83 (m,2H), 7.16-7.20 (m, 1H), 9.86 (s, br, 1H), 10.06 (s, 1H). LCMS (MethodA): 0.169 min, MS: ES+136.1 (M+1).

5-(Benzyloxy)-4-(4-hydroxyisoindoline-2-carbonyl)-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate)

A stirred solution of Intermediate 22 (5 g, 8.59 mmol, 1.0 eq.) in DMF(50 mL) at 0° C. was treated with HATU (4.89 g, 12.88 mmol, 1.5 eq),DIPEA (2.21 g, 17.18 mmol, 2.0 eq.) and stirred for 15 min.Isoindolin-4-ol hydrochloride (1.6 g, 9.45 mmol, and 1.1 eq) was addedand the reaction mixture stirred at room temperature for 1 h. Theresulting reaction mixture was diluted with ethyl acetate (180 mL) andwashed with cold brine solution (4×150 mL). The organic layer was driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude material was purified by flash chromatography (product was elutedby 11% ethyl acetate in hexane) yielding the title compound (4 g, 5.72mmol, Yield: 67%).

LCMS (Method A): 2.709 min, MS: ES+700.03 (M+1).

5-(Benzyloxy)-4-methyl-6-(4-((tetrahydrofuran-3-yl)oxy)isoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate)

5-(Benzyloxy)-4-(4-hydroxyisoindoline-2-carbonyl)-6-methyl-1,3-phenylene-bis(4-methylbenzenesulfonate) (0.5 g, 0.71 mmol, 1 eq.), tetrahydrofuran-3-ol (CAS:453-20-3) (0.062 g, 0.71 mmol, 1.0 eq.) and triphenyl phosphine (0.37 g,1.43 mmol, 2.0 eq.) in THF (0.5 mL) were sonicated for 15 min at roomtemperature. DIAD (98%) (0.28 g, 1.43 mmol, 2.0 eq.) was added to theresulting reaction mixture dropwise under nitrogen atmosphere at 60° C.The resulting mixture was stirred at 60° C. for 30 min, allowed to coolto room temperature, poured into ice-water (70 mL) and extracted withethyl acetate (3×75 mL). The combined organic layer was dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudematerial was purified by flash chromatography (product was eluted inDCM) to give the title compound (0.26 g, 3.38 mmol, Yield: 47%).

LCMS (Method A): 2.677 min, MS: ES+770.2 (M+1).

((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone

A stirred solution of5-(benzyloxy)-4-methyl-6-(4-((tetrahydrofuran-3-yl)oxy)isoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (0.25 g, 3.25 mmol, 1.0 eq.) in EtOH:water (2.5 mL, 1: 1) at room temperature was treated with aqueous KOH(0.72 g, 13.00 mmol, 40 eq. in minimum water). The resulting reactionmixture was heated to 60° C. and stirred for 2 h. The reaction mixturewas allowed to cool to room temperature, poured into ice cooled water(50 mL) and neutralized with diluted HCl and extracted with ethylacetate (4×50 mL). The combined organic layer was dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude materialwas purified by flash chromatography (product eluted in 5.7% methanol inDCM) yielding the title compound (0.022 g, 0.04 mmol, Yield: 15%).

¹H NMR (DMSO-d6, 400 MHz), compound is a mixture of rotamers: δ1.88-1.99 (M, 1H), 1.97 (2 singlets, 3H), 2.14-2.33 (m, 1H), 3.66-3.94(m, 4H), 4.23-4.25 (m, 1H), 4.42-4.74 (m, 4H), 4.90-4.92 (m, 1H),5.02-5.10 (m, 1H), 6.29 (2 singlets, 1H), 6.82-6.97 (m, 2H), 7.21-7.36(m, 6H), 9.49-9.59 (m, 2H). LCMS (Method A): 1.869 min, MS: ES+462.2(M+1).

Example 89: (4-(Azetidin-3-yl methoxy)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl) methanone (Reaction SchemeShown in FIG. 5) t-Butyl3-(((2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindolin-4-yl)oxy)methyl)azetidine-1-carboxylate

A mixture of5-(benzyloxy)-4-(4-hydroxyisoindoline-2-carbonyl)-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (0.7 g, 1.00 mmol, 1.0 eq), t-butyl3-(hydroxymethyl)azetidine-1-carboxylate (CAS: 142253-56-3) (0.18 g,1.00 mmol, 1.0 eq) and triphenyl phosphine (0.52 g, 2.00 mmol, 2.0 eq)in THF (0.7 mL, minimum solvent to make a paste) was sonicated for 15min at 35° C. The mixture was warmed to 60° C. and treated dropwise withDIAD (98%) (0.4 g, 2.00 mmol, 2.0 eq.), the resulting reaction mixturewas stirred at 60° C. under a nitrogen atmosphere for 1 h. The reactionmixture was allowed to cool to room temperature, poured into ice-coldwater (80 mL) and extracted with ethyl acetate (4×80 mL). The combinedorganic was dried over sodium sulphate, filtered, and concentrated underreduced pressure. The crude material (1.2 g) was purified by normalphase flash chromatography (230-400 mesh silica; product eluted in neatDCM) to give the title compound (0.5 g, 0.57 mmol, Yield: 57%).

LCMS (Method A): 2.860 min, MS ES+769.5 (M−100).

t-Butyl3-(((2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)oxy)methyl)azetidine-1-carboxylate

A stirred solution of t-butyl3-(((2-(2-(benzyloxy)-3-methyl-4,6-bis(tosyloxy)benzoyl)isoindolin-4-yl)oxy)methyl)azetidine-1-carboxylate(0.5 g, 0.57 mmol, 1.0 eq.) in EtOH (5 mL) at room temperature wastreated with an aqueous solution of KOH (1.29 g, 23.00 mmol, 40 eq.) inwater (5 mL). The reaction mixture was heated to 60° C. for 2 h thenallowed to cool to room temperature, poured into water (80 mL) andneutralized with dil.HCl, extracted with ethyl acetate (3×80 mL) and thecombined organic layer dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude material was purified by flashchromatography (product eluted with 6% methanol in DCM) followed byprep. TLC (5% methanol in DCM) yielding the title compound (0.09 g, 0.16mmol, Yield: 28%).

¹H NMR (DMSO-d6, 400 MHz), compound is a mixture of rotamers: δ1.36-1.40 (2 singlets, 9H), 1.97-1.99 (2 singlets, 3H), 2.86-2.97 (m,1H), 3.35-3.72 (m, 3H), 3.73-4.04 (m, 2H), 4.11-4.29 (m, 2H), 4.41-4.74(m, 4H), 4.89-4.92 (m, 1H), 6.30 (s, 1H), 6.83-6.96 (m, 2H), 7.22-7.36(m, 6H), 9.50-9.59 (m, 2H). LCMS (Method A): 2.188 min, purity: 100% MSES+: 461.3 (M−100).

(4-(Azetidin-3-ylmethoxy)isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone

A stirred solution of t-butyl3-(((2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)oxy)methyl)azetidine-1-carboxylate(0.08 g, 0.14 mmol, 1.0 eq.) in DCM (2.4 mL) at 0° C. was treated withTFA (0.8 mL) added dropwise. The reaction mixture was stirred at roomtemperature for 1 h, concentrated under reduced pressure, poured intowater (15 mL), neutralized with saturated sodium bicarbonate solution,and extracted with ethyl acetate (4×15 mL). The combined organic layerwas dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude material was purified by trituration [n-pentane (20ml)] and dried under high vacuum to give the title compound as an offwhite solid (0.030 g, 0.06 mmol, Yield: 46%).

¹H NMR (DMSO-d6, 400 MHz, 335K), compound is a mixture of rotamers: δ1.99 (s, 3H), 3.41-3.43 (m, 1H), 3.72-3.73 (m, 1H), 3.95-4.20 (m, 4H),4.40-4.92 (m, 7H), 6.30 (s, 1H), 6.86-7.02 (m, 2H), 7.24-7.35 (m, 6H),9.53-9.62 (m, 2H). LCMS (Method A): 1.474 min, MS ES+: 461.3 (M+1).

Example 90:(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone(Reaction scheme shown in FIG. 6)5-(Benzyloxy)-4-methyl-6-(4-(pyrimidin-5-ylmethoxy)isoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate)

A mixture of5-(Benzyloxy)-4-(4-hydroxyisoindoline-2-carbonyl)-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (0.5 g, 0.71 mmol, 1.0 eq.),pyrimidin-5-ylmethanol (0.078 g, 0.71 mmol, 1.0 eq.) (CAS: 25193-95-7)and triphenyl phosphine (0.37 g, 1.43 mmol, 2.0 eq.) in THF (0.5 mL,minimum solvent to make a paste) was sonicated for 15 min at 35° C. Thereaction mixture was warmed to 60° C. and treated dropwise with DIAD(98%) (0.28 g, 1.43 mmol, 2.0 eq.). The reaction mixture was stirred at60° C. under a nitrogen atmosphere for 1 h then allowed to cool to roomtemperature, poured into water (130 mL) and extracted with ethyl acetate(3×100 mL). The combined organic layer was dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The crude material was purifiedby flash chromatography (3.4% methanol in DCM) to give the titlecompound (0.35 g, 0.45 mmol, Yield: 62%) which was carried forward tothe next step without purification.

LCMS (Method A): 2.465 min, 2.586 min, MS: ES+778.1 (M+1).

(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone

A stirred solution of5-(benzyloxy)-4-methyl-6-(4-(pyrimidin-5-ylmethoxy)isoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (0.2 g, 0.25 mmol, 1.0 eq.) in DCM:Methanol (9:1) (2 mL) at room temperature was treated with NaOH (0.05 g,1.26 mmol, 5.0 eq.) and stirred for 1 h. The resulting reaction mixturewas poured into water (25 mL), neutralized with dil. HCl and extractedwith ethyl acetate (3×25 mL). The combined organic layer was dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudematerial was purified by prep. TLC (10% MeOH in DCM) followed by prep.HPLC purification yielding (0.012 g, 0.024 mmol, Yield: 9%).

High temperature ¹H NMR (DMSO-d6, 400 MHz, 340K), compound is a mixtureof rotamers: δ 1.96 (s, 3H), 4.50-4.51 (m, 2H), 4.66-4.75 (m, 4H),5.18-5.28 (m, 2H), 6.27 (2 singlets, 1H), 6.84-7.02 (m, 2H), 7.22-7.32(m, 6H), 8.78 (s, 1H), 8.90 (s, 1H), 9.08-9.14 (m, 1H). LCMS (Method A):1.678 min, MS ES+484.27 (M+1).

Example 91:1-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)azetidine-3-carbonitrile

1-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)azetidine-3-carbonitrile

A stirred solution of(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-bromoisoindolin-2-yl)methanone(0.3 g, 0.66 mmol, 1.0 eq.) in 1,4-dioxane (3 mL) at room temperaturewas treated with azetidine-3-carbonitrile (0.117 g, 0.99 mmol, 1.5 eq)(CAS: 345954-83-8) and K₃PO₄ (0.420 g, 1.90 mmol, 3 eq). The reactionmixture was degassed using N₂ gas for 10 min. Pd₂(dba)₃ (0.060 g, 0.06mmol, 0.1 eq) and X-phos (0.063 g, 0.13 mmol, 0.2 eq) were added and theresulting reaction mixture heated to 100° C. and stirred for 1 h undermicrowave irradiation. The resulting reaction mixture was filteredthrough celite bed, poured into ice-cold water (100 mL) and extractedusing ethyl acetate (3×100 mL). The combined organic layer was driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by flash chromatography (product eluted in 3%MeOH: DCM) followed by prep. HPLC purification (MeCN: MeOH: IPA)yielding the title compound (0.005 g, 0.010 mmol, Yield: 1.61%).

¹H NMR (DMSO-d6, 400 MHz), compound is a mixture of rotamers: δ 1.97 (2singlets, 3H), 3.49-3.75 (m, 1H), 3.84-4.07 (m, 3H), 4.07-4.08 (m, 1H),4.18-4.22 (m, 1H), 4.34-4.39 (m, 1H), 4.47-4.74 (m, 3H), 4.91 (m, 1H),6.30-6.36 (m, 2H), 6.66-6.83 (m, 1H), 7.11-7.19 (m, 1H), 7.26-7.37 (m,5H), 9.51-9.58 (m, 2H). LCMS (Method A): 1.862 min, MS ES+456.22 (M+1).

Example 92:(4,6-Dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone(Reaction Scheme Shown in FIG. 7)4-Formyl-5-methoxy-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate)(Intermediate 54)

A stirred solution of 4-formyl-5-hydroxy-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (2.0 g, 4.19 mmol, 1.0 eq) Intermediate 2in DMF (20 mL) at room temperature was treated with K₂CO₃ (1.45 g, 10.49mmol, 2.5 eq) and CH₃I (0.89 g, 6.29 mmol, 1.5 eq). The resultingreaction mixture was heated to 65° C. and stirred for 4 h. The reactionmixture was poured into ice-cold water (100 mL) and extracted in ethylacetate (3×100 mL). The combined organic layer was dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude materialwas purified by flash chromatography (product eluted in 12% ethylacetate in hexane) yielding as an off-white solid (1.2 g, Yield: 58.29%,2.44 mmol).

¹H NMR (DMSO-d6, 400 MHz): δ 1.86 (s, 3H), 2.44 (s, 3H), 2.46 (s, 3H),3.65 (s, 3H), 6.68 (s, 1H), 7.48-7.53 (m, 4H), 7.70-7.76 (m, 4H), 9.93(s, 1H). LCMS (Method A): 2.588 min. MS: ES+491.12 (M+1).

2-Methoxy-3-methyl-4,6-bis(tosyloxy)benzoic acid (Intermediate 60)

A stirred solution of 4-formyl-5-methoxy-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (1.1 g, 2.24 mmol, 1.0 eq.) (Intermediate54) in MeCN: Water (1:1) (20 mL) at room temperature was treated withNaH₂PO₄ (0.806 g, 6.72 mmol, 3.0 eq.) and NaClO₂ (0.74 g, 8.2 mmol, 3.7eq.) and the reaction mixture stirred at room temperature for 3 h. Theresulting reaction mixture was evaporated, diluted with water (20 mL),acidified using 1N HCl solution and extracted with ethyl acetate (2×100mL). The combined organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduce pressure yielding the title compound as an offwhite solid (1.0 g, 1.97 mmol. Yield: 88.1%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.85 (s, 3H), 2.45 (s, 6H), 3.64 (s, 3H),6.66 (s, 1H), 7.49-7.52 (m, 4H), 7.72-7.73 (m, 4H), 13.60 (bs, 1H). LCMS(Method A): 2.137 min, MS: ES+507.02

5-Methoxy-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate)

A stirred solution of 2-methoxy-3-methyl-4,6-bis(tosyloxy)benzoic acid(0.5 g, 0.987 mmol, 1.0 eq) (Intermediate 60) in DMF (5 mL) at 0° C. wastreated with HATU (0.487 g, 1.28 mmol, 1.3 eq) and DIPEA (0.637 g, 4.93mmol, 5.0 eq) and stirred for 10 mins. 5-((4-methylpiperazin-1-yl)methyl) isoindoline hydrochloride (0.290 g, 1.08 mmol, 1.1 eq.) wasadded and the resulting reaction mixture was stirred at room temperaturefor 16 h. The reaction mixture was poured into ice-cold water (50 mL)and extracted in ethyl acetate (3×100 mL). The combined organic layerwas washed with brine solution (30 mL), dried over Na₂SO₄, filtered, andconcentrated under vacuum. The crude material was purified by flashchromatography (eluting product 3% methanol in DCM) yielding the titlecompound as an off white solid (0.350 g, Yield: 49.24%, 0.486 mmol)which was progressed to the next step.

(4,6-Dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

A stirred solution of 5-methoxy-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl) isoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (0.3 g, 0.416 mmol, 1.0 eq.) in EtOH: H₂O(4 mL) (3:1) at room temperature was treated with KOH (0.933 g, 16.66mmol, 40 eq.) and heated to 60° C. and stirred for 2 h. The resultingreaction mixture cooled to room temperature and concentrated undervacuum. The obtained crude material was acidified using saturatedsolution of KHSO₄. The aqueous layer was concentrated under vacuum andextracted using 20% IPA: CHCl₃ (3×30 mL). The combined organic layer wasdried over Na₂SO₄, filtered, and concentrated under reduced pressure.The crude material was purified by prep HPLC (0.1% formic acid water inacetonitrile) yielding the title compound as an off-white solid (0.02 g,0.048 mmol, Yield: 11.7%).

High temperature ¹H NMR (DMSO-d6, 400 MHz, 340K): δ 1.95 (s, 3H), 2.18(s, 3H), 2.30-2.50 (m, 8H), 3.44-3.46 (m, 2H), 3.64 (s, 3H), 4.50 (s,2H), 4.75 (s, 2H), 6.26 (s, 1H), 7.18-7.20 (m, 2H), 7.28-7.29 (m, 1H),9.19 (bs, 2H). LCMS (Method A): 0.854 min, MS: ES+412.32 (M+1).

Example 93:(2-Ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone(Reaction Scheme Shown in FIG. 8)5-Ethoxy-4-formyl-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate)(Intermediate 55)

A stirred solution of 4-formyl-5-hydroxy-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (2.0 g, 4.19 mmol, 1.0 eq) Intermediate 2in DMF (20 mL) at room temperature was treated with K₂CO₃ (2.89 g, 20.9mmol, 5.0 eq) and ethyl bromide (2.89 g, 6.29 mmol, 1.5 eq) and theresulting reaction mixture stirred for 16 h. The reaction mixture waspoured into ice-cold water (100 mL) and extracted in ethyl acetate (3×30mL). The combined organic layer washed with cold water (2×50 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude material was purified by flash chromatography (product eluted with13% ethyl acetate in hexane) yielding as off-white solid (1.5 g, 2.97mmol. Yield: 71.0%).

¹H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ1.07-1.27 and 1.20-1.24 (m, 3H), 1.77 and 1.85 (singlets, 3H) 2.44-2.50(singlets, 6H), 3.35-3.40 and 3.78-3.82 (m, 2H), 6.44 and 6.71(singlets, 1H), 7.48-7.53 (m, 4H), 7.69-7.80 (m, 4H), 9.86 and 9.92(singlets, 1H). LCMS (Method A): 2.721 min, MS: ES+505.7 (M+1).

2-Ethoxy-3-methyl-4,6-bis(tosyloxy)benzoic acid (Intermediate 61)

A solution of 5-ethoxy-4-formyl-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (1.4 g, 2.77 mmol, 1.0 eq.) (Intermediate55) in MeCN:Water (1:1) (15 mL) at room temperature was treated withNaH₂PO₄ (1.16 g, 9.71 mmol, 3.5 eq.) and NaClO₂ (1.25 g, 13.87 mmol, 5.0eq.) and the reaction mixture stirred for 16 h. The reaction mixture wasevaporated and the crude material diluted with water (30 mL), acidifiedusing dil. HCl solution and extracted with ethyl acetate (3×30 mL). Thecombined organic layer was dried over Na₂SO₄, filtered, and concentratedunder reduced pressure; the crude material was purified by flashchromatography using silica gel eluting product with 10% ethyl acetatein hexane yielding the title compounds as an off white solid (0.6 g,1.15 mmol. Yield: 41.7%).

¹H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ1.16-1.24 (m, 3H), 1.84 and 2.00 (singlets, 3H), 2.44-2.51 (s, br, 6H),3.78-3.83 and 4.00-4.06 (m, 2H), 6.66 and 6.68 (singlets, 1H), 7.49-7.58(m, 4H), 7.71-7.80 (m, 4H), 13.59 (s, 1H). LCMS (Method A): 2.455 min,MS: ES+521.12 (M+1).

5-Ethoxy-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate)

A stirred solution of 2-ethoxy-3-methyl-4,6-bis(tosyloxy)benzoic acid(0.4 g, 0.768 mmol, 1.0 eq) (Intermediate 61) in DMF (2 mL) at 0° C. wastreated with HATU (0.438 g, 1.01 mmol, 1.5 eq) and DIPEA (0.495 g, 3.84mmol, 5.0 eq) and stirred for 10 mins. 5-((4-methylpiperazin-1-yl)methyl) isoindoline hydrochloride (0.226 g, 0.845 mmol, 1.1 eq.)dissolved in DMF (1 mL) was added dropwise and the reaction mixturestirred at room temperature for 16 h. The reaction mixture was pouredinto ice-cold water (20 mL) and extracted in ethyl acetate (2×30 mL).The combined organic layer was washed with cold water (3×50 mL), driedover Na₂SO₄, filtered, and concentrated under vacuum. The crude materialwas purified by flash chromatography (eluting product with 4% methanolin DCM) yielding the title compound as an off white solid (0.350 g,0.476 mmol. Yield: 62%) which was progressed directly to the next step.

(2-Ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

A stirred solution of5-ethoxy-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (0.320 g, 0.436 mmol, 1.0 eq.) in EtOH:H₂O (3 mL) (2:1) at room temperature was treated with KOH (0.978 g,17.44 mmol, 40 eq.) and heated to 60° C. for 3 h. The resulting reactionmixture was allowed to cool to room temperature, poured into water (10mL) and acidified using saturated solution of KHSO₄ and extracted using20% IPA in CHCl₃ (3×20 mL). The combined organic layer was dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudematerial was purified by prep HPLC (0.1% formic acid/water inacetonitrile) yielding the title compound as an off-white solid (0.025g, 0.058 mmol, Yield: 13.5%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.17 (t, J=6.8 Hz, 3H), 1.92 (s, 3H),2.13-2.14 (m, 3H), 2.15-2.50 (m, 8H), 3.41-3.44 (m, 2H), 3.78-3.84 (m,2H), 4.42-4.53 (m, 2H), 4.72 (s, br, 2H), 6.24 (s, 1H), 7.16-7.22 (m,2H), 7.29-7.32 (m, 1H), 9.40 (s, 1H, D₂0 exchangeable), 9.48 (s, 1H, D₂0exchangeable). LCMS (Method A): 1.021 min, MS: ES+426.32 (M+1).

Example 94:(2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone(Reaction Scheme Shown in FIG. 9)5-(Cyclohexylmethoxy)-4-formyl-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 56)

A stirred solution of4-formyl-5-hydroxy-6-methyl-1,3-phenylene-bis(4-methylbenzenesulfonate)(2.0 g, 4.19 mmol, 1.0 eq) in DMF (20 mL) at 0° C. was treated withK₂CO₃ (2.89 g, 20.9 mmol, 5.0 eq) and bromomethyl cyclohexane (1.11 g,6.29 mmol, 1.5 eq) and stirred for 10 mins. The reaction mixture wasgradually raised to room temperature and stirred for 16 h. The reactionmixture was poured into ice-cold water (20 mL) and extracted in ethylacetate (3×30 mL). The combined organic layer was dried over Na₂SO₄,filtered, and concentrated under vacuum. Crude material was purified byflash chromatography (product eluted with 12% ethyl acetate in hexane)yielding the title compound (1.4 g, 2.44 mmol. Yield: 58.3%).

¹H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ0.97-1.00 (m, 2H), 1.11-1.26 (m, 3H), 1.67-1.73 (m, 5H), 1.77 and 1.83(singlets, 3H), 2.33-2.45 (singlets, 6H), 3.49 and 3.70 (m, 2H), 5.77(s, 1H), 6.44 and 6.70 (singlets, 1H), 7.48-7.53 (m, 4H), 7.71-7.81 (m,4H), 9.86 and 9.90 (singlets, 1H). LCMS (Method A): 3.250 min, MS:ES+573.13 (M+1).

2-(Cyclohexylmethoxy)-3-methyl-4,6-bis(tosyloxy)benzoic acid(Intermediate 62)

A solution of 5-(cyclohexylmethoxy)-4-formyl-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (1.4 g, 2.44 mmol, 1.0 eq.) (Intermediate56) in MeCN:Water (1:1) (15 mL) at room temperature was treated withNaH₂PO₄ (1.02 g, 8.55 mmol, 3.5 eq.) and NaClO₂ (1.10 g, 12.22 mmol, 5.0eq.) and stirred for 16 h. The mixture was evaporated and the crudematerial diluted with water (30 mL) and extracted with ethyl acetate(3×30 mL). The combined organic layer was dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The crude material was purifiedby flash chromatography (eluting product using 15% ethyl acetate inhexane) yielding the title compound (0.950 g, 1.61 mmol. Yield: 66.4%).

¹H NMR (DMSO-d6, 400 MHz): δ0.95-1.10 (m, 2H), 1.11-1.22 (m, 3H),1.61-1.69 (m, 6H), 1.82 (s, br, 3H), 2.44 (s, br, 6H), 3.54 (m, br, 2H),4.03 (q, J=6.8 Hz, 14.0 Hz, 2H), 6.69 (s, 1H), 7.49-7.52 (m, 4H),7.70-7.73 (m, 4H), 13.59 (s, 1H). LCMS (Method A): 2.657 min, MS:ES+589.2 (M+1).

5-(Cyclohexylmethoxy)-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate)

A stirred solution of2-(Cyclohexylmethoxy)-3-methyl-4,6-bis(tosyloxy)benzoic acid (0.4 g,0.679 mmol, 1.0 eq) (Intermediate 62) in DMF (2 mL) at 0° C. was treatedwith HATU (0.387 g, 1.01 mmol, 1.5 eq) and DIPEA (0.438 g, 3.39 mmol,5.0 eq) for 10 mins. 5-((4-methylpiperazin-1-yl) methyl) isoindolinehydrochloride (0.217 g, 0.815 mmol, 1.1 eq.) dissolved in DMF (1 mL) wasadded dropwise at 0-5° C. The resulting reaction mixture was graduallyraised to room temperature and stirred for 16 h. The reaction mixturewas poured onto ice-cold water (50 mL) and extracted with ethyl acetate(2×50 mL). The combined organic layer was washed with cold water (3×100mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. Thecrude material was purified by flash chromatography (eluting productwith 8% methanol in DCM) yielding the title compound as an off whitesolid (0.350 g, 0.436 mmol. Yield: 62.0%) which was used directly in thenext step.

(2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

A stirred solution of5-(cyclohexylmethoxy)-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (0.330 g, 0.414 mmol, 1.0 eq.) in EtOH:H₂O (2:1) was treated with KOH (0.923 g, 16.45 mmol, 40 eq.) at roomtemperature. The reaction mixture was heated to 60° C. and stirred for 3h. The reaction mixture was allowed to cool to room temperature, pouredinto water (20 mL), acidified using KHSO₄ solution) and extracted in 20%IPA in CHCl₃ (3×30 mL). The combined organic layer was dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudematerial was purified by prep HPLC (0.1% formic acid water inacetonitrile) yielding the title compound as an off-white solid (0.030g, 0.060 mmol, Yield: 14.8%).

¹H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ0.88-0.94 (m, 2H), 1.02-1.24 (m, 3H), 1.56-1.60 (m, 6H), 1.91 (s, 3H),2.18 and 2.19 (singlets, 3H), 2.29-2.50 (m, 6H), 3.63 (m, 2H), 4.49 (s,2H), 4.70 (s, 2H), 6.24 (s, 1H), 7.10-7.22 (m, 2H), 7.30-7.33 (m, 1H),9.37 (s, br, 1H), 9.47 (s, br, 1H). 4 protons obscured by solvent peaks.LCMS (Method A): 1.372 min, MS: ES+494.37 (M+1).

Example 95:(2-(Cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone(Reaction Scheme Shown in FIG. 10)5-(Cyclopropylmethoxy)-4-formyl-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 57)

A stirred solution of 4-formyl-5-hydroxy-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) Intermediate 2 (1.0 g, 2.09 mmol, 1.0 eq)in DMF (10 mL) at room temperature was treated with K₂CO₃ (0.72 g, 5.24mmol, 2.5 eq) and (bromomethyl)cyclopropane (0.420 g, 3.14 mmol, 1.5eq). The reaction mixture was heated to 70° C. and stirred for 6 h. Thereaction mixture was poured into ice-cold water (50 mL) and extracted inethyl acetate (3×50 mL). The combined organic layer was washed withwater (2×50 mL) and brine solution (2×50 mL). The combined organic layerwas dried over Na₂SO₄, filtered, and concentrated under vacuum. Thecrude material was purified by flash chromatography (product eluted in13.1% ethyl acetate: hexane) yielding the title compound (0.86 g, 1.62mmol. Yield: 77.2%).

¹H NMR (DMSO-d6, 400 MHz): δ 0.075-0.18 (m, 2H), 0.40-0.49 (m, 2H),0.96-1.01 (m, 1H), 1.82 (s, 3H), 2.42 and 2.44 (2 singlets, 6H),3.53-3.61 (m, 2H), 6.74 (s, 1H), 7.46-7.51 (m, 4H), 7.68-7.75 (m, 4H),9.95 (s, 1H). LCMS (Method A): 2.726 min. MS: ES+531.1 (M+1).

2-(Cyclopropylmethoxy)-3-methyl-4,6-bis(tosyloxy)benzoic acid(Intermediate 63)

A solution of 5-(cyclopropylmethoxy)-4-formyl-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (0.86 g, 1.62 mmol, 1.0 eq.) (Intermediate57) in MeCN:Water (1:1) (10 mL) at room temperature was treated withNaH₂PO₄ (0.583 g, 4.86 mmol, 3.0 eq.) and NaClO₂ (0.542 g, 5.99 mmol,3.7 eq.). The reaction mixture was stirred at room temperature for 4 h,poured into ice-cold water (50 mL), acidified using dil. HCl andextracted with ethyl acetate (3×50 mL). The combined organic layer wasdried over Na₂SO₄, filtered, and concentrated under reduced pressure.The crude material was triturated using n-pentane (10 mL), diethyl ether(10 mL) and further dried using high vacuum yielding to give the titlecompound as an off white sticky solid (0.610 g, 1.11 mmol. Yield:68.9%).

¹H NMR (DMSO-d6, 400 MHz): δ 0.12-0.16 (m, 2H), 0.44-0.47 (m, 2H),1.00-1.10 (m, 1H), 1.83 (s, 3H), 2.43 (s, 6H), 3.58-3.64 (m, 2H), 6.69(s, 1H), 7.48-7.51 (m, 4H), 7.70-7.77 (m, 4H), 13.58 (bs, 1H). LCMS(Method A): 2.487 min, MS: ES+569.2 (M+23).

5-(Cyclopropylmethoxy)-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate)

A stirred solution of2-(cyclopropylmethoxy)-3-methyl-4,6-bis(tosyloxy)benzoic acid (0.510 g,0.933 mmol, 1.0 eq) (Intermediate 63) in DMF (5 mL) at 0° C. was treatedwith HATU (0.460 g, 1.21 mmol, 1.3 eq) and DIPEA (0.80 mL, 4.66 mmol,5.0 eq). 5-((4-methylpiperazin-1-yl)methyl)isoindoline hydrochloride(0.274 g, 1.02 mmol, 1.1 eq.) was added and the reaction mixture raisedto room temperature and stirred for 16 h. The reaction mixture waspoured with ice-cold water (100 mL) and extracted in ethyl acetate(3×110 mL). The combined organic layer was dried over Na₂SO₄, filtered,and concentrated under vacuum. The crude material was purified by columnchromatography (eluting product with 20% EtOAc in Hexane) yielding thetitle compound (0.490 g, 0.64 mmol. Yield: 69.1%) which was progressedto the next step.

(2-(Cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

A stirred solution of5-(cyclopropylmethoxy)-4-methyl-6-(5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carbonyl)-1,3-phenylenebis(4-methylbenzenesulfonate) (0.47 g, 0.62 mmol, 1.0 eq.) in EtOH: H₂O(1:1) at room temperature was treated with KOH (1.38 g, 24.59 mmol, 40eq.). The reaction mixture was heated to 60° C. and stirred for 3 h. Theresulting reaction mixture was allowed to cool to room temperature,poured into water (20 mL) and acidified using KHSO₄ solution andextracted into EtOAc (3×30 mL). The aqueous layer was further extractedwith 10% IPA in CHCl₃(3×50 mL). The combined organic layer was driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude material was purified by prep HPLC using 0.05% NH₃ in water:acetonitrile. The pure fractions were lyophilized yielding the titlecompound as an off-white solid (0.050 g, 0.11 mmol. Yield: 17.9%).

¹H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ 0.17 (m,2H), 0.43 (m, 2H), 1.04-1.06 (m, 1H), 1.92 (s, 3H), 2.12 and 2.13(singlets, 3H), 2.30-2.49 (m, 8H), 3.40-3.43 (m, 2H), 3.58 (m, 2H),4.45-4.48 (m, 2H), 4.70-4.71 (m, br, 2H), 6.23 (s, 1H), 7.16-7.22 (m,2H), 7.29-7.32 (m, 1H), 9.47 (bs, 2H, D₂0 exchangeable). LCMS (MethodB): 4.732 min, MS: ES+452.4 (M+1).

Example 96:(2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Reaction Scheme Shownin FIG. 11) 5-(Cyclohexylmethoxy)-4-(6-((dimethyl amino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate)

To a stirred solution2-(cyclohexylmethoxy)-3-methyl-4,6-bis(tosyloxy)benzoic acid(Intermediate 62) (0.3 g, 0.51 mmol, 1 eq) at 0° C. in DMF (3 mL) wereadded HATU (0.29 g, 0.76 mmol, 1.5 eq) and DIPEA (0.13 g, 1.02 mmol, 2eq) and the mixture stirred for 15 min. N,N-dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)methanamine(Intermediate 43) (0.12 g, 0.66 mmol, 1.3 eq) was added and stirringcontinued at room temperature for 16 h. The reaction mixture was pouredinto ice cold water (60 mL) and extracted using ethyl acetate (3×60 mL).The combined organic layer was washed with ice cold water (3×80 mL),dried over Na₂SO₄, filtered and concentrated under vacuum. Crudematerial was purified by flash chromatography (product eluted in 4% MeOHin DCM) to give the title compound as a yellow solid (0.3 g, Yield:77.4%) which was used directly in the next step.

Example 96:(2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone

A stirred solution of 5-(cyclohexylmethoxy)-4-(6-((dimethyl amino)methyl)-1, 2, 3, 4-tetrahydro-isoquinoline-2-carbonyl)-6-methyl-1,3-phenylene bis (4-methylbenzenesulfonate) (0.27 g, 0.35 mmol, 1 eq.) inEtOH: H₂O (2:1) (3 mL) at room temperature was treated with KOH (0.790g, 14.1 mmol, 40 eq.). The reaction mixture was heated to 60° C. andstirred for 2 h, poured into ice cold water (50 mL), neutralized usingsaturated solution of KHSO₄ solution and extracted in ethyl acetate(3×60 mL). The combined organic layer was dried over Na₂SO₄, filteredand concentrated under vacuum. The crude material was purified by columnchromatography followed by Prep HPLC purification (Method C) to give thetitle compound as an off white solid (0.012 g, Yield: 7.5%). ¹H NMR Hightemperature (DMSO-d6, 400 MHz, 351K): δ 0.85-0.87 (m, 2H), 1.01-1.12 (m,3H), 1.51-1.53 (m, 6H), 1.92 (s, 3H), 2.15 (s, 6H), 2.66-2.81 (m, 2H),3.33 (s, 2H), 3.45-3.48 (m, 2H), 4.42-4.66 (m, 2H), 6.21 (s, 1H), 7.06(s, 3H), 9.37 (s, 2H). LCMS (Method D): 1.806 min, 97.60%, 254 nm, MS:ES+453.4 (M+1). HPLC (Method A): 4.639 min, 97.99%, 230 nm.

Synthesis of Intermediates

In one approach (Scheme 2), substituted aromatic carboxylic acid offormula [II] may be prepared by Pinnick oxidation of a substitutedaromatic aldehyde of formula [IV] with an oxidising agent such as sodiumchlorite (NaClO₂), in monosodium phosphate buffered solution (NaH₂PO₄)aqin a polar solvent such as acetonitrile or THF. The reaction is suitablyconducted at RT or by thermal heating. After reaction work up, typicallyby a liquid-liquid extraction, the reaction product is purified by flashcolumn chromatography, reverse phase preparative HPLC orre-crystallisation. Intermediate substituted aromatic aldehyde compoundsof general formula [IV] may be prepared by reaction of an intermediatebis-Ts protected phenol intermediate compound of general formula [V]with a halide of general formula [VI] in a polar solvent such as DMF orDMA with a base such as K₂CO₃ or Cs₂CO₃. The reaction is suitablyconducted under thermal heating. After reaction work up, typically by aliquid-liquid extraction, the reaction product is purified by flashcolumn chromatography, reverse phase preparative HPLC orre-crystallisation. Intermediate bis-Ts protected phenol intermediatecompounds of general formula [V] are prepared by reaction of atri-phenol compound of general formula [VII] with tosyl chloride, in apolar solvent such as acetone or THF with a base such as K₂CO₃ orCs₂CO₃. The reaction is suitably conducted at 0° C. or RT. Afterreaction work up, typically by a liquid-liquid extraction, the reactionproduct is purified by flash column chromatography, reverse phasepreparative HPLC or re-crystallisation, to yield Intermediate bis-Tsprotected phenol intermediate compounds of general formula [V].

In one approach (Scheme 3), bis-tosyl protected phenol intermediatecompounds of general formula [V] were prepared by reaction of a1,3,5-triphenolbenzaldehyde derivative of general formula [VII] withpara-toluenesulfonylchloride in a polar solvent such as acetonitrile oracetone, with a base such as K₂CO₃ or Na₂CO₃. The reaction is suitablyconducted at RT or by thermal heating. After reaction work up, typicallyby a liquid-liquid extraction, the reaction product was purified byflash column chromatography, reverse phase preparative HPLC orre-crystallisation.

Synthesis of 4-formyl-5-hydroxy-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 1)

To a solution of 2,4,6-trihydroxybenzaldehyde (CAS #487-70-7) (5 g, 32.2mmol, 1.0 eq) in acetone (200 mL) was added K₂CO₃ (22.27 g, 161 mmol,5.0 eq) and p-toluene sulphonyl chloride (12.90, 67.7 mmol, 2.1 eq) atroom temperature. The reaction mixture was heated at 60° C. for 4 h. Theresulting reaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure. The crude material was diluted withwater (300 mL) and extracted in EtOAc (3×400 mL). The combined organiclayer was washed with brine solution (200 mL), dried over sodiumsulphate and concentrated under reduced pressure to give crude materialwhich was purified by column chromatography using silica gel (elutingproduct using 8.7% ethyl acetate in hexane) yielding4-formyl-5-hydroxy-1,3-phenylene bis(4-methylbenzenesulfonate)(Intermediate 1) as a yellow solid (5.9 g, Yield: 39.3%).

¹H NMR (DMSO-d⁶, 400 MHz): δ 2.44 (d, J=2.4 Hz, 6H), 6.38 (d, J=2.4 Hz,1H), 6.66 (d, J=2.4 Hz, 1H), 7.47-7.54 (m, 4H), 7.69 (d, J=8.0 Hz, 2H),7.78 (d, J=8.4 Hz, 2H), 9.89 (s, 1H), 11.52 (s, 1H). LCMS: 2.441 min,MS: ES+461.30 (M−1)

The following compounds were prepared according to the method describedabove using the indicated intermediates

Intermediate No. Name Structure Data 2 4-formyl-5-hydroxy-6-methyl-1,3-phenylene bis(4- methylbenzenesulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 1.77 (s, 1H), 2.45 (d, J = 8.0 Hz, 6H),6.45 (s, 1H), 7.51-7.54 (m, 4H), 7.74-7.81 (m, 4H), 9.86 (s, 1H), 11.82(s, 1H). LCMS (Method A): 2.582 min, MS: ES+ 477 (M + 1) Using2,4,6-trihydroxy- 3-methylbenzaldehyde (CAS-55743-13-0) 34-ethyl-6-formyl-5- hydroxy-1,3-phenylene bis(4- methylbenzenesulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 0.89 (t, J = 7.6 Hz, 3H), 2.35-2.37 (m,2H), 2.45 (d, 7.2 Hz, 6H), 6.46 (s, 1H), 7.51-7.55 (m, 4H), 7.77-7.82(m, 4H), 9.86 (s, 1H), 11.88 (s, 1H). LCMS (Method A): 2.727 min, MS:ES+ 491 (M + 1) Using 3-ethyl-2,4,6- trihydroxybenzaldehyde (CAS412021-94-4)

In one approach (Scheme 4), bis-tosyl protected alkoxy-phenolintermediate compounds of general formula [IV] were prepared by reactionof a bis-tosyl protected phenol intermediate of general formula [V] witha compound of general formula [VI] with a base such as Cs₂CO₃ or K₂CO₃in a polar aprotic solvent such as DMF or DMA. The reaction is suitablyconducted at RT or by thermal heating. After reaction work up, typicallyby a liquid-liquid extraction, the reaction product was purified byflash column chromatography, reverse phase preparative HPLC orre-crystallisation

Synthesis of 5-(cyclopentyloxy)-4-formyl-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 4)

To a solution of 4-formyl-5-hydroxy-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 1) (3 g, 6.48 mmol, 1.0 eq)in DMF (20 mL) was added Cs₂CO₃ (2.10 g, 6.44 mmol, 1.0 eq) andbromocyclopentane (1.44 g, 9.66 mmol, 1.5 eq) at room temperature. Thereaction mixture was heated to 80° C. and stirred for 3 h. The cooledreaction mixture was diluted with water (200 mL) and extracted in EtOAc(3×250 mL). The combined organic layer was washed with brine solution(200 mL), dried over sodium sulphate and concentrated under reducepressure. The obtained crude material was purified by columnchromatography using silica gel (eluting product using 10.2% ethylacetate in hexane) yielding 5-(cyclopentyloxy)-4-formyl-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 4) as a yellow oil (2.1 g,Yield: 61.0%). ¹H NMR (DMSO-d⁶, 400 MHz): δ 1.53-1.62 (m, 8H), 2.42 (d,J=4.8 Hz, 6H), 4.60-4.80 (m, 1H), 6.45 (d, J=1.60 Hz, 1H), 6.75 (d,J=1.6 Hz, 1H), 7.46-7.52 (m, 4H), 7.66-7.76 (m, 4H), 9.92 (s, 1H). LCMS:2.788 min, MS: ES+531.17 (M+1)

The following compounds were prepared according to the Method describedabove using the indicated intermediates

Int. No. Name Structure Data 5 5-(benzyloxy)-4- formyl-1,3- phenylenebis(4- methylbenzene- sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 2.44 (d, J = 2.4 Hz, 6H), 5.15 (s, 2H),6.46 (d, J = 2.8 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.40-7.41 (m, 4H),7.46-7.51 (m, 4H), 7.65 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H),9.99 (s, 1H). LCMS (Method A): 2.594 min, MS: ES+ 575.06 (M + 23) Using4-formyl-5-hydroxy-1,3- phenylene bis(4- methylbenzenesulfonate)(Intermediate 1) and benzylbromide 6 5-(benzyloxy)-4-formyl-6-methyl-1,3- phenylene bis(4- methylbenzene- sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 1.83 (d, J = 9.20 Hz, 3H), 2.44 (d, J = 8.0Hz, 6H), 4.80 (s, 2H), 6.75 (s, 1H), 7.31- 7.37 (m, 5H), 7.49-7.54 (m,4H), 7.71-7.77 (m, 4H), 9.87 (s, 1H). LCMS (Method A): 2.697 min, MS:ES+ 589.10 (M + 23) Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylenebis(4- methylbenzenesulfonate) Intermediate 2 and benzylbromide 75-(benzyloxy)-4- ethyl-6-formyl-1,3- phenylene bis(4- methylbenzene-sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 0.89 (t, J = 7.6 Hz, 3H), 2.32-2.34 (q,2H), 2.45 (d, J = 9.2 Hz, 6H), 4.82 (s, 2H), 6.79 (s, 1H), 7.35-7.40 (m,5H), 7.51-7.55 (m, 4H), 7.73-7.80 (m, 4H), 9.91 (s, 1H). LCMS (MethodA): 2.763 min, MS: ES+ 603.15 (M + 23) Using 4-ethyl-6-formyl-5-hydroxy-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 3 andbenzylbromide 8 4-formyl-5-(pyridin- 2-ylmethoxy)-1,3- phenylene bis(4-methylbenzene- sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 2.44 (d, J = 4.8 Hz, 6H), 5.19 (s, 2H),6.50 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.36-7.39 (m, 4H),7.48-7.54 (m, 1H), 7.67- 7.75 (m, 4H), 7.84-7.89 (m, 1H), 8.57 (d, J =4.8, 1H), 10.05 (s, 1H). LCMS (Method A): 2.339 min, MS: ES+ 554.1(M + 1) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4-methylbenzenesulfonate) (Intermediate 1) and 2- (bromomethyl)pyridinehydrobromide 9 4-formyl-5- (pyrimidin-2- ylmethoxy)-1,3- phenylenebis(4- methylbenzene- sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 2.42-2.44 (m, 6H), 5.38 (s, 2H), 6.49 (d, J= 2.0 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 7.44-7.51 (m, 5H), 7.66- 7.68(m, 4H), 8.12 (d, J = 5.2 Hz, 2H), 10.83 (s, 1H). LCMS (Method A): 2.243min, MS: ES+ 555.0 (M + 1) Using 4-formyl-5-hydroxy-1,3- phenylenebis(4- methylbenzenesulfonate) (Intermediate 1) and 2-(bromomethyl)-pyrimidine hydrochloride 10 4-formyl-5-(1-phenylethoxy)-1,3- phenylene bis(4- methylbenzene- sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 1.48 (d, J = 6.0 Hz, 3H), 2.41-2.45 (m,6H), 5.58- 5.68 (m, 1H), 6.40 (d, J = 1.60 Hz, 1H), 6.91 (d, J = 2.0 Hz,1H), 7.31-7.38 (m, 5H), 7.39-7.42 (m, 4H), 7.50- 7.59 (m, 4H), 10.05 (s,1H). LCMS (Method A): 2.800 min, MS: ES+ 589.1 (M + 23) Using4-formyl-5-hydroxy-1,3- phenylene bis(4- methylbenzenesulfonate)(Intermediate 1) and (1- bromoethyl)benzene 11 5-((4-fluorobenzyl)oxy)-4- formy-1,3- phenylene bis(4- methylbenzene-sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 2.44 (s, 6H), 5.14 (s, 2H), 6.46 (d, J =2.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 7.21- 7.26 (m, 2H), 7.45-7.52 (m,6H), 7.65-7.67 (m, 2H), 7.74- 7.76 (m, 2H), 9.99 (s, 1H). LCMS (MethodA): 2.636 min, MS: ES+ 593.10 (M + 23) Using 4-formyl-5-hydroxy-1,3-phenylene bis(4- methylbenzenesulfonate) (Intermediate 1) and 4-fluorobenzylbromide 12 4-formyl-5-((4- methoxybenzyl)oxy)- 1,3-phenylenebis(4- methylbenzene- sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 2.44 (s, 6H), 3.77 (s, 3H), 5.06 (s, 2H),6.44 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 8.40 Hz, 2H), 7.08 (d, J = 2.0Hz, 1H), 7.33-7.35 (m, 2H), 7.46- 7.52 (m, 4H), 7.65 (d, J = 9.2 Hz,2H), 7.76 (d, J = 8.0 Hz, 2H), 9.95 (s, 1H). LCMS (Method A): 2.573 min,MS: ES+ 605.1 (M + 23) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4-methylbenzenesulfonate) (Intermediate 1) and 4- methoxybenzylbromide 134-formyl-5-((3- methylbenzyl)oxy)- 1,3-phenylene bis(4- methylbenzene-sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 2.32 (s, 3H), 2.44 (d, J = 2.4 Hz, 6H),5.10 (s, 2H), 6.45 (d, J = 1.6 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H),7.17-7.29 (m, 4H), 7.47-7.51 (m, 4H), 7.65 (d, J = 8.4 Hz, 2H), 7.73 (d,J = 8.4 Hz, 2H), 9.99 (s, 1H). LCMS (Method A): 2.691 min, MS: ES+589.20 (M + 23) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4-methylbenzenesulfonate) (Intermediate 1) and 3- methylbenzylbromide 144-formyl-5- (pyrimidin-4- ylmethoxy)-1,3- phenylene bis(4-methylbenzene- sulfonate)

LCMS (Method A): 2.508 min, MS: ES+ 555.1 (M + 1) Using4-formyl-5-hydroxy-1,3- phenylene bis(4- methylbenzenesulfonate)(Intermediate 1) and 4- (Bromomethyl)pyrimidine 15 tert-butyl3-((2-formyl-3,5- bis(tosyloxy)phenox y)methyl)-1H- pyrazole-1- carboxylate

1H NMR (DMSO-d6, 400 MHz): δ 1.58 (s, 9H), 2.44 (s, 6H), 5.15 (s, 2H),6.48 (d, 2.0 Hz, 1H), 6.58 (d, J = 2.8 Hz, 1H), 7.11 (d, 2.0 Hz, 1H),7.47-7.52 (m, 4H), 7.66 (d, J = 8.4 Hz, 2H), 7.67 (d, 8.4 Hz, 2H), 8.29(d, 2.8 Hz, 1H), 9.97 (s, 1H). LCMS (Method A): 2.672 min, MS: ES+665.00 (M + 23) Using 4-formyl-5-hydroxy-1,3- phenylene bis(4-methylbenzenesulfonate) (Intermediate 1) and tert-butyl3-(bromomethyl)-1H- pyrazole-1-carboxylate 16 5-((4-fluorobenzyl)oxy)-4- formyl-6-methyl-1,3- phenylene bis(4-methylbenzene- sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 1.81 (s, 3H), 2.44 (d, J = 7.6 Hz, 6H),4.80 (s, 2H), 6.74 (s, 1H), 7.18-7.23 (m, 2H), 7.36-7.40 (m, 2H), 7.49-7.54 (m, 4H), 7.71-7.77 (m, 4H), 9.86 (s, 1H). LCMS (Method A): 2.817min, MS: ES+ 607.1 (M + 23) Using 4-formyl-5-hydroxy-6-methyl-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 2 and4- fluorobenzylbromide 17 4-formyl-6-methyl-5- ((3- methylbenzyl)oxy)-1,3-phenylene bis(4- methylbenzene- sulfonate)

1H NMR (DMSO-d6, 400 MHz): δ 1.82 (s, 3H), 2.30 (s, 3H), 2.45 (d, J =8.0 Hz, 6H), 4.75 (s, 2H), 6.72 (s, 1H), 7.09 (d, J = 7.2 Hz, 1H), 7.17(d, J = 7.6 Hz, 2H), 7.23-7.27 (m, 1H), 7.48-7.53 (m, 4H), 7.70- 7.76(m, 4H), 9.87 (s, 1H). LCMS (Method A): 2.825 min, MS: ES+ 603.1 (M +23) Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate 2 and 3- methylbenzylbromide 184-formyl-6-methyl-5- (pyridin-2- ylmethoxy)-1,3- phenylene bis(4-methylbenzene- sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 1.83 (s, 3H), 2.44 (d, J = 8.0 Hz, 6H),4.87 (s, 2H), 6.74 (s, 1H), 7.36-7.39 (m, 1H), 7.47-7.53 (m, 5H0, 7.70-7.76 (m, 4H), 7.81-7.86 (m, 1H), 8.54 (d, J = 4.0 Hz, 1H), 9.92 (s, 1H).LCMS (Method A): 2.420 min, MS: ES+ 568.1 (M + 1) Using4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate 2 and 2- (bromomethyl)pyridinehydrobromide 19 4-formyl-6-methyl-5- ((1-methyl-1H- pyrazol-3-yl)methoxy)-1,3- phenylene bis(4- methylbenzene- sulfonate)

1H NMR (DMSO-d6, 400 MHz): δ 1.82 (s, 3H), 2.43 (s, 3H), 2.45 (s, 3H),3.79 (s, 3H), 4.76 (s, 2H), 6.10 (s, 1H), 6.70 (s, 1H), 7.48-7.53 (m,4H), 7.63-7.78 (m, 5H), 9.79 (s, 1H). LCMS (Method E): 2.395 min, MS:ES+ 571.11 (M + 1) Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylenebis(4- methylbenzenesulfonate) Intermediate 2 and 3-(chloromethyl)-1-methyl-1H- pyrazole hydrochloride 544-Formyl-5-methoxy- 6-methyl-1,3- phenylene bis(4- methylbenzene-sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 1.86 (s, 3H), 2.44 (s, 3H), 2.46 (s, 3H),3.65 (s, 3H), 6.68 (s, 1H), 7.48-7.53 (m, 4H), 7.70-7.76 (m, 4H), 9.93(s, 1H). LCMS (Method A): 2.588 min. MS: ES+ 491.12 (M + 1). Using4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 2) 55 5-Ethoxy-4-formy 1-6-methyl-1,3- phenylene bis(4- methylbenzene- sulfonate)

¹H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ1.07-1.27 and 1.20-1.24 (m, 3H), 1.77 and 1.85 (singlets, 3H) 2.44-2.50(singlets, 6H), 3.35-3.40 and 3.78-3.82 (m, 2H), 6.44 and 6.71(singlets, 1H), 7.48-7.53 (m, 4H), 7.69-7.80 (m, 4H), 9.86 and 9.92(singlets, 1H). LCMS (Method A): 2.721 min, MS: ES+ 505.7 (M + 1). Using4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4-methylbenzenesulfonate) (Intermediate 2) 56 5- (Cyclohexylmethoxy)-4-formyl-6-methyl- 1,3-phenylene bis(4- methylbenzene- sulfonate)

¹H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ0.97-1.00 (m, 2H), 1.11-1.26 (m, 3H), 1.67- 1.73 (m, 5H), 1.77 and 1.83(singlets, 3H), 2.33-2.45 (singlets, 6H), 3.49 and 3.70 (m, 2H), 5.77(s, 1H), 6.44 and 6.70 (singlets, 1H), 7.48-7.53 (m, 4H), 7.71-7.81 (m,4H), 9.86 and 9.90 (singlets, 1H). LCMS (Method A): 3.250 min, MS: ES+573.13 (M + 1). Using 4-formyl-5-hydroxy-6- methyl-1,3-phenylene-bis(4-methylbenzenesulfonate) 57 5- (Cyclopropylmethoxy)- 4-formyl-6-methyl-1,3-phenylene bis(4- methylbenzene- sulfonate)

¹H NMR (DMSO-d6, 400 MHz): δ 0.075-0.18 (m, 2H), 0.40-0.49 (m, 2H),0.96- 1.01 (m, 1H), 1.82 (s, 3H), 2.42 and 2.44 (2 singlets, 6H),3.53-3.61 (m, 2H), 6.74 (s, 1H), 7.46-7.51 (m, 4H), 7.68- 7.75 (m, 4H),9.95 (s, 1H). LCMS (Method A): 2.726 min, MS: ES+ 531.1 (M + 1). Using4-formyl-5-hydroxy-6- methyl-1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate 2

In one approach (Scheme 5), substituted aromatic carboxylic acids offormula [II] were prepared by a Pinnick oxidation of a substitutedaromatic aldehyde of formula [IV] with an oxidising agent such as sodiumchlorite (NaClO₂), in monosodium phosphate buffered solution (NaH₂PO₄)aqin a polar solvent such as acetonitrile or THF. The reaction is suitablyconducted at RT or by thermal heating. After reaction work up, typicallyby a liquid-liquid extraction, the reaction product was purified byflash column chromatography, reverse phase preparative HPLC orre-crystallisation.

Synthesis of 2-(cyclopentyloxy)-4,6-bis(tosyloxy)benzoic acid(Intermediate 20)

To a solution of 4 5-(cyclopentyloxy)-4-formyl-1,3-phenylenebis(4-methylbenzenesulfonate) (0.8 g, 1.51 mmol, 1 eq) in acetonitrile:water (1:1) (20 mL) was added NaH₂PO₄ (0.36 g, 3.00 mmol, 2 eq) andNaClO₂ (0.496 g, 5.48 mmol, 3.6 eq) at room temperature. The reactionmixture was stirred at room temperature for 16 h. Solvent was removedunder vacuum and the isolated crude material diluted with water (70 mL),acidified using formic acid, and extracted in EtOAc (3×150 mL). Thecombined organic layer was dried over sodium sulphate and concentratedunder reduced pressure. The obtained crude material was purified byflash chromatography using silica gel (eluting product using 35.3% ethylacetate in hexane) yielding 2-(cyclopentyloxy)-4,6-bis(tosyloxy)benzoicacid (Intermediate 20) as an oil (0.35 g, Yield: 42.5%). ¹H NMR(DMSO-d⁶, 400 MHz): δ 1.43-1.61 (m, 6H), 1.66-1.70 (m, 2H), 2.43 (d,J=9.2 Hz, 6H), 4.68-4.69 (m, 1H), 6.52 (d, J=2.0 Hz, 1H), 6.61 (d, J=1.6Hz, 1H), 7.46-7.51 (m, 4H), 7.69-7.74 (m, 4H), 13.29 (s, 1H). LCMS:2.395 min, MS: ES+569.11 (M+23).

The following compounds were prepared according to the Methods describedabove using the indicated intermediates

No Name Structure Data 21 2-(benzyloxy)-4,6- bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 2.42 (s, 6H), 4.96 (s, 2H), 6.53 (d, J =1.6 Hz, 1H), 6.68-6.70 (m, 1H), 7.33-7.36 (m, 5H), 7.41-7.48 (m, 4H),7.67-7.75 (m, 4H), 13.70 (brs, 1H). LCMS (Method A): 2.293 min, MS: ES+591.1 (M + 23) Using 5-(benzyloxy)-4-formyl-1,3- phenylene bis(4-methylbenzenesulfonate) Intermediate 5 22 2-(benzyloxy)-3- methyl-4,6-bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 1.84 (s, 3H), 2.45 (d, J = 1.20 Hz, 6H),4.80 (s, 2H), 6.73 (s, 1H), 7.33-7.39 (m, 5H), 7.50-7.53 (m, 4H),7.72-7.75 (m, 4H), 13.74 (s, 1H). LCMS (Method A): 2.464 min, MS: ES+605.20 (M + 23) Using 5-(benzyloxy)-4-formyl-6- methyl-1,3-phenylenebis(4- methylbenzenesulfonate) Intermediate 6 23 2-(benzyloxy)-3-ethyl-4,6- bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 0.92 (t, J = 7.6 Hz, 3H), 2.35-2.37 (m,2H), 2.45 (d, J = 2.4 Hz, 6H), 4.86 (s, 2H), 6.76 (s, 1H), 7.35- 7.38(m, 5H), 7.50-7.54 (m, 4H), 7.74-7.77 (m, 4H), 13.83 (s, 1H). LCMS(Method A): 2.510 min, MS: ES+ 619.10 (M + 23) Using5-(benzyloxy)-4-ethyl-6- formyl-1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate 7 24 2-(pyridin-2- ylmethoxy)-4,6-bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 2.44 (d, J = 7.2 Hz, 6H), 5.11 (s, 2H),6.55 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 7.35-7.38 (m, 2H),7.47-7.50 (m, 4H), 7.67- 7.73 (m, 4H), 7.82-7.86 (m, 1H), 8.56 (t, J =1.6 Hz, 1H), 13.54 (s, 1H). LCMS (Method A): 2.069 min, MS: ES+ 570.1(M + 1) Using 4-formyl-5-(pyridin-2- ylmethoxy)-1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate 8 25 2-(pyrimidin-2-ylmethoxy)-4,6- bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 2.43 (d, J = 3.2 Hz, 6H), 5.22 (s, 2H),6.54 (d, J = 2.0 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 7.44-7.51 (m, 5H),7.65-7.70 (m, 4H), 8.81 (d, J = 4.8 Hz, 2H), 13.50 (s, 1H). LCMS (MethodA): 2.087 min, MS: ES+ 571.1 (M + 1) Using 4-formyl-5-(pyrimidin-2-ylmethoxy)-1,3-phenylene bis(4- methylbenzenesulfonate) Intermediate 926 2-(1-phenylethoxy)- 4,6- bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 1.40 (d, J = 6.0 Hz, 3H), 2.42 (d, J = 4.8Hz, 6H), 5.45-5.49 (m, 1H), 6.44 (d, J = 1.6 Hz, 1H), 6.68 (s, 1H),7.27-7.33 (m, 5H), 7.35- 7.56 (m, 6H), 7.65 (d, J = 9.0 Hz, 2H), 13.48(s, 1H). LCMS (Method A): 2.529 min, MS: ES+ 605.1 (M + 23) Using4-formyl-5-(1- phenylethoxy)-1,3-phenylene bis(4-methylbenzenesulfonate)Intermediate 10 27 2-((4- fluorobenzyl)oxy)- 4,6- bis(tosyloxy)benzoicacid

¹H NMR (DMSO-d6, 400 MHz): δ 2.44 (d, J = 4.0 Hz, 6H), 5.05 (s, 2H),6.50 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 7.22 (t, J = 8.8 Hz,2H), 7.37-7.40 (m, 2H), 7.48- 7.51 (m, 4H), 7.67 (d, J = 7.6 Hz, 2H),7.73 (d, J = 8.4 Hz, 2H), 13.42 (s, 1H). LCMS (Method A): 2.355 min, MS:ES+ 609.1 (M + 23) Using 5-((4-fluorobenzyl)oxy)-4- formyl-1,3-phenylenebis(4- methylbenzenesulfonate) Intermediate 11 28 2-((4-methoxybenzyl)oxy)- 4,6- bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 2.44 (d, J = 2.4 Hz, 6H), 3.76 (s, 3H),4.95 (s, 2H), 6.50 (d, J = 2.0 Hz, 1H), 6.89-6.94 (m, 3H), 7.28 (t, J =8.8 Hz, 2H), 7.41-7.56 (m, 24), 7.64-7.69 (m, 2H), 7.73- 7.78 (m, 2H),13.38 (s, 1H). LCMS (Method A): 2.329 min, MS: ES+ 621.1 (M + 23) Using4-formyl-5-((4- methoxybenzyl)oxy)-1,3- phenylene bis(4-methylbenzenesulfonate) Intermediate 12 29 2-((3- methylbenzyl)oxy)-4,6- bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 2.30 (s, 3H), 2.44 (d, J = 3.6 Hz, 6H),5.00 (s, 2H), 6.50 (d, J = 1.2 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H),7.10-7.15 (m, 3H), 7.25-7.28 (m, 1H), 7.48-7.51 (m, 4H), 7.67 (d, J =8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 13.42 (s, 1H). LCMS (Method A):2.397 min, MS: ES+ 605.1 (M + 1) Using 4-formyl-5-((3-methylbenzyl)oxy)-1,3-phenylene bis(4-methylbenzenesulfonate)Intermediate 13 30 2-(pyrimidin-4- ylmethoxy)-4,6- bis(tosyloxy)benzoicacid

¹H NMR (DMSO-d6, 400 MHz): δ 2.43 (d, J = 5.6 Hz, 6H), 5.13 (s, 2H),6.59 (d, J = 1.6 Hz, 1H), 7.43- 7.49 (m, 6H), 7.67-7.74 (m, 4H), 8.82(d, J = 5.2 Hz, 1H), 9.16 (d, J = 0.8 Hz, 1H), 13.74 (s, 1H). LCMS(Method A): 2.312 min, MS: ES+ 571.1 (M + 1) Using4-formyl-5-(pyrimidin-4- ylmethoxy)-1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate 14 31 2-((1-(tert-butoxycarbonyl)-1H- pyrazol-3- yl)methoxy)-4,6- bis(tosyloxy)benzoicacid

1H NMR (DMSO-d6, 400 MHz): δ 1.58 (s, 9H), 2.44 (s, 6H), 5.15 (s, 2H),6.48 (d, 2.0 Hz, 1H), 6.58 (d, 2.8 Hz, 1H), 7.11 (d, 2.0 Hz, 1H),7.47-7.52 (m, 4H), 7.66 (d, 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 8.29(d, 2.8 Hz, 1H), 9.97 (s, 1H). LCMS (Method A): 2.672 min, MS: ES+665.00 (M + 23) Using tert-butyl 3-((2-formyl-3,5-bis(tosyloxy)phenoxy)methyl)-1H- pyrazole-1-carboxylate Intermediate 1532 2-((4- fluorobenzyl)oxy)-3- methyl-4,6- bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 1.84 (s, 3H), 2.45 (d, J = 1.2 Hz, 6H),4.79 (s, 2H), 6.72 (s, 1H), 7.19-7.23 (m, 2H), 7.37-7.40 (m, 2H),7.50-7.53 (m, 4H), 7.72- 7.74 (m, 4H), 13.75 (s, 1H). LCMS (Method A):2.517 min, MS: ES+ 623.1 (M + 23) Using 5-((4-fluorobenzyl)oxy)-4-formyl-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate16 33 3-methyl-2-((3- methylbenzyl)oxy)- 4,6- bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 1.84 (s, 3H), 2.30 (s, 3H), 2.44 (s, 6H),4.75 (s, 2H), 6.71 (s, 1H), 7.13-7.16 (m, 3H), 7.23-7.25 (m, 1H),7.49-7.52 (m, 4H), 7.73 (d, J = 8.4 Hz, 4H), 13.75 (s, 1H). LCMS (MethodA): 2.583 min, MS: ES+ 619.1 (M + 23) Using 4-formyl-6-methyl-5-((3-methylbenzyl)oxy)-1,3-phenylene bis(4-methylbenzenesulfonate)Intermediate 17 34 3-methyl-2-(pyridin- 2-ylmethoxy)-4,6-bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 1.85 (s, 3H), 2.44 (d, J = 1.6 Hz, 6H),4.89 (s, 2H), 6.74 (s, 1H), 7.37-7.40 (m, 1H), 7.48-7.52 (m, 5H),7.72-7.74 (m, 4H), 7.85- 7.89 (m, 1H), 8.54 (d, J = 4.4 Hz, 1H), 13.75(s, 1H). LCMS (Method A): 2.112 min, MS: ES+ 584.1 (M + 1) Using4-formyl-6-methyl-5- (pyridin-2-ylmethoxy)-1,3- phenylene bis(4-methylbenzenesulfonate) Intermediate 18 35 3-Methyl-2-((1-methyl-1H-pyrazol- 3-yl)methoxy)-4,6- bis(tosyloxy)benzoic acid

1H NMR (DMSO-d6, 400 MHz): δ 1.80 (s, 3H), 2.45 (s, 6H), 3.83 (s, 3H),4.72 (s, 2H), 6.14 (d, 2.0 Hz, 1H), 6.71 (s, 1H), 7.49- 7.52 (m, 4H),7.64 (d, 2.0 Hz, 1H), 7.63-7.78 (m, 4H). LCMS (Method E): 2.249 min, MS:ES+ 587.16 (M + 1) Using 4-formyl-6-methyl-5-((1-methyl-1H-pyrazol-3-yl)methoxy)- 1,3-phenylene bis(4-methylbenzenesulfonate) Intermediate 19 36 2-((1-tosyl-1H-1,2,3-triazol-4- yl)methoxy)-4,6- bis(tosyloxy)benzoic acid

LCMS (Method A): 2.228 min, MS: ES+ 560.10 (M − 155, tosyl) Using4-formyl-5-((1-tosyl-1H- 1,2,3-triazol-4-yl)methoxy)-1,3- phenylenebis(4- methylbenzenesulfonate) Intermediate 38 58 2-(2-(Benzyloxy)-4,6-dihydroxy-3- methylbenzoyl) isoindoline-5- carboxylic acid

LCMS (Method A): 1.555 min, MS: ES+ 420.20 (M + 1). Using methyl2-(2-(benzyloxy)-3- methyl-4,6- bis(tosyloxy)benzoyl)isoindoline-5-carboxylate 59 2-(2-(Benzyloxy)- 4,6-dihydroxy-3- methylbenzoyl)isoindoline-4- carboxylic acid

¹H NMR (DMSO-d6, 400 MHz) compound is a mixture of rotamers: δ 1.98 (s,br, 3H), 4.11- 4.13 (m, 2H), 4.46-4.72 (m, 2H), 4.85-5.01 (m, 2H), 6.31(s, 1H), 7.23-7.96 (m, 8H), 9.51-9.59 (m, 2H), 13.02 (s, br, 1H). LCMS(Method A): 1.728 min, MS: ES+ 420.17 (M + 1). Using methyl2-(2-(benzyloxy)-3- methyl-4,6- bis(tosyloxy)benzoyl)isoindoline-4-carboxylate 60 2-Methoxy-3-methyl- 4,6- bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 1.85 (s, 3H), 2.45 (s, 6H), 3.64 (s, 3H),6.66 (s, 1H), 7.49-7.52 (m, 4H), 7.72-7.73 (m, 4H), 13.60 (bs, 1H). LCMS(Method A): 2.137 min, MS: ES+ 507.02 Using 4-formyl-5-methoxy-6-methyl-1,3-phenylene bis(4- methylbenzenesulfonate) (Intermediate 54) 612-Ethoxy-3-methyl- 4,6- bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): Compound is a mixture of rotamers: δ1.16-1.24 (m, 3H), 1.84 and 2.00 (singlets, 3H), 2.44- 2.51 (s, br, 6H),3.78-3.83 and 4.00-4.06 (m, 2H), 6.66 and 6.68 (singlets, 1H), 7.49-7.58(m, 4H), 7.71-7.80 (m, 4H), 13.59 (s, 1H). LCMS (Method A): 2.455 min,MS: ES+ 521.12 (M + 1). Using 5-ethoxy-4-formyl-6-methyl- 1,3-phenylenebis(4- methylbenzenesulfonate) (Intermediate 55) 62 2-(Cyclohexylmethoxy)- 3-methyl-4,6- bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 0.95-1.10 (m, 2H), 1.11-1.22 (m, 3H),1.61-1.69 (m, 6H), 1.82 (s, br, 3H), 2.44 (s, br, 6H), 3.54 (m, br, 2H),4.03 (q, J = 6.8 Hz, 14.0 Hz, 2H), 6.69 (s, 1H), 7.49- 7.52 (m, 4H),7.70-7.73 (m, 4H), 13.59 (s, 1H). LCMS (Method A): 2.657 min, MS: ES+589.2 (M + 1). Using 5-(cyclohexylmethoxy)-4-formyl-6-methyl-1,3-phenylene bis(4-methylbenzenesulfonate)(Intermediate 56) 63 2- (Cyclopropylmethoxy)- 3-methyl-4,6-bis(tosyloxy)benzoic acid

¹H NMR (DMSO-d6, 400 MHz): δ 0.12-0.16 (m, 2H), 0.44-0.47 (m, 2H),1.00-1.10 (m, 1H), 1.83 (s, 3H), 2.43 (s, 6H), 3.58-3.64 (m, 2H), 6.69(s, 1H), 7.48-7.51 (m, 4H), 7.70-7.77 (m, 4H), 13.58 (bs, 1H). LCMS(Method A): 2.487 min, MS: ES+ 569.2 (M + 23). Using5-(cyclopropylmethoxy)-4- formyl-6-methyl-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 57)

Additional Procedures Synthesis of4-formyl-5-(prop-2-yn-1-yloxy)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 37) (Reaction Scheme Shownin FIG. 12)

To a solution of 4-formyl-5-hydroxy-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 1) (2.0 g, 4.32 mmol, 1.0eq) in DMF (20 mL) was added K₂CO₃ (1.8 g, 13.0 mmol, 2.0 eq) at 000under a nitrogen atmosphere. 3-Bromoprop-1-yne (CAS #106-96-7) (0.613 g,5.2 mmol, 1.5 eq) was added dropwise to the reaction mixture at 0° C.The reaction was stirred at room temperature overnight. The resultingreaction mixture was diluted with water (100 mL) and extracted withethyl acetate (3×30 mL) yielding4-formyl-5-(prop-2-yn-1-yloxy)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 37) (3.0 g, 74% yield). Thismaterial was progressed to the next step without further purification.

¹H NMR (CDCl3-d6, 400 MHz): δ 2.48 (s, 3H), 2.49 (s, 3H), 3.51 (s, 1H),4.73-4.75 (m, 2H), 6.60 (d, J=2.0 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H),7.35-7.40 (m, 4H), 7.75-7.78 (m, 4H), 10.09 (s, 1H). LCMS (Method B):2.820 min, MS: ES+502.01 (M+1)

Synthesis of4-formyl-5-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 38)

To a solution of 4-formyl-5-(prop-2-yn-1-yloxy)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 37) (2.0 g, 4.00 mmol, 1.0eq) in toluene (20 mL) was added copper(I) thiophene-2-carboxylate(0.030, 0.16 mmol, 0.04 eq) at 0° C. under nitrogen atmosphere.p-Toluenesulfonyl azide (0.0.945 g, 4.8 mmol, 1.2 eq) was added to thereaction mixture at 0° C. The reaction was stirred at room temperaturefor 2 h and the resulting reaction mixture diluted with water (100 mL)and extracted with ethyl acetate (3×300 mL). The combined organic layerwas dried under reduced pressure. The obtained crude material waspurified by column chromatography (product eluted with 1% MeOH in DCM)yielding4-formyl-5-((1-tosyl-1H-1,2,3-triazol-4-yl)methoxy)-1,3-phenylenebis(4-methylbenzenesulfonate) (Intermediate 38) (2.8 g, 19% yield).

¹H NMR (CDCl3, 400 MHz): δ 2.47 (s, 3H), 2.49 (s, 6H), 5.17 (s, 2H),6.59 (d, J=2.0 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H), 7.33-7.43 (m, 6H),7.71-7.75 (m, 4H), 8.03-8.06 (m, 2H), 8.31 (s, 1H), 10.05 (s, 1H). LCMS(Method B): 3.02 min, MS: ES+699.52 (M+1)

Synthesis ofN,N-Dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)methanamine(Intermediate 42) (Reaction Scheme Shown in FIG. 13) 2-(t-Butyl)7-methyl 3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate

To a stirred solution of t-butyl7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.0 g, 16.0 mmol, 1.0eq) in MeOH (66 mL) and MeCN (16 mL) in an autoclave was added TEA (3.23g, 3.20 mmol, 2.0 eq) at room temperature. The reaction mixture wasdegassed (N₂ gas) for 15 min. PdCl₂(dppf) (0.93 g, 1.28 mmol, 0.08 eq)was added and 22 kg/cm² CO_((gas)) pressure was applied with heat (100°C.) for 16 h. The reaction mixture was concentrated under vacuum and thecrude material purified by flash column chromatography (220-400 silica;product eluted by 2.5% ethyl acetate in hexane) to give the titlecompound (3.5 g, 12.02 mmol, Yield: 75%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.43 (s, 9H), 2.84 (t, J=6 Hz, 2H), 3.56(t, J=5.6 Hz, 2H), 3.81 (s, 3H), 4.56 (m, 2H), 7.31 (d, J=8 Hz, 1H),7.74-7.78 (m, 2H). LCMS (Method A): 2.111 min, MS: ES+192.18 (M+1-100).

2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid

To a stirred solution of 2-(t-butyl) 7-methyl3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate (3.5 g, 12.02 mmol, 1.0eq.) in MeOH: water (9:1) (50 mL) was added NaOH (2.40 g, 60.1 mmol, 5.0eq.) at room temperature and the mixture stirred for 3 h. The resultingmixture was poured into water (60 mL) and neutralized (dil. HCl),extracted with ethyl acetate (3×90 mL) and the combined organic layerdried over Na₂SO₄, filtered, and concentrated under reduced pressure.Crude material was purified by trituration using n-pentane (250 mL)yielding the title compounds as a brown oil (3.5 g, 12.63 mmol. Yield:100%).

¹H NMR (DMSO-d6, 400 MHz): δ ppm 1.42 (s, 9H), 2.75 (t, J=5.6 Hz, 2H),3.52-3.55 (m, 2H), 4.48 (brs, 2H), 7.05 (d, J=7.6 Hz, 1H), 7.66-7.694(m, 2H). —COOH proton not observed. LCMS (Method A): 1.783 min, MS:ES+178.17 (M−100)

t-Butyl 7-(dimethylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

A stirred solution of2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid(2.5 g, 9.2 mmol, 1.0 eq) in DMF (25 mL) at 0° C. was treated with HATU(5.14 g, 13.53 mmol, 1.5 eq), DIPEA (2.32 g, 18.04 mmol, 2.0 eq) anddimethyl amine (2M in THF) (0.44 g, 99.23 mmol, 1.1 eq.) added dropwise.The reaction was allowed to warm to room temperature and stirred for 1h. Reaction completion was monitored by TLC (DCM: MeOH; 9:1). Thereaction mixture was diluted with ethyl acetate (45 mL), washed withchilled brine solution (4×50 mL); the organic layer dried Na₂SO₄,filtered and concentrated under vacuum. The crude material was purifiedby flash chromatography (product eluted with 4% methanol in DCM)yielding the title compound as an off white solid (2.1 g, 11.49 mmol.Yield: 76%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.44 (s, 9H), 2.80 (t, J=6 Hz, 2H),2.92-2.97 (2 singlets, 6H), 3.57 (t, J=6 Hz, 2H), 4.52 (s, 2H),7.21-7.22 (m, 3H). LCMS (Method A): 1.687 min, MS: ES+249.05 (M−56).

N,N-Dimethyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (Intermediate42a)

tert-Butyl7-(dimethylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.1 g,6.90 mmol, 1.0 eq.) in DCM (21 mL) at 0° C. was treated dropwise withTFA (2.1 mL) and the reaction mixture stirred at room temperature for 1h. The resulting reaction mixture was concentrated under reducedpressure, poured into water (60 mL) and neutralized with 1M NaOHsolution and extracted using DCM (5×60 mL). The combined organic layerwas dried over Na₂SO₄, filtered and concentrated under reduced pressureto give the title compound as an oil (1.8 g, 8.81 mmol. Yield: 78%).

¹H NMR (DMSO-d6, 400 MHz): 2.74-2.85 (t, br, 2H), 2.92-2.94 (singlets,broad, 6H), 2.93-3.03 (t, br, 2H), 3.91 (s, br, 2H), 7.08-7.30 (m, 3H).LCMS (Method B): 0.463 min, MS: ES+205.25 (M+1).

N,N-Dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)methanamine(Intermediate 42)

N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (Intermediate42a) (0.2 g, 0.97 mmol, 1.0 eq.) in THF (2 ml) at 0° C. was treateddropwise with LiAlH₄ (1M in THF) (2.84 mL, 2.9 eq). The resultingreaction mixture was heated to 80° C. and stirred for 3 h. Reactioncompletion was monitored by TLC (methanol: DCM 8:2). The reactionmixture was allowed to cool to 0° C. and basified (1M NaOH), extractedwith ethyl acetate (3×25 mL) and the combined organic layer dried overNa₂SO₄, filtered and concentrated under reduced pressure yielding thetitle compound as yellow oil (0.18 g, 0.94 mmol, Yield: 97%).

¹H NMR (DMSO-d6, 400 MHz): 2.64-2.67 (t, br, 2H), 2.92-2.94 (t, br, 2H),3.23-3.34 (2 singlets, br, 6H), 3.81 (s, br, 2H), 6.90-7.04 (m, 3H).LCMS (Method B): 1.52 min, MS: ES+191.28 (M+1).

Synthesis ofN,N-Dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)methanamine(Intermediate 43) (Reaction Scheme Shown in FIG. 14) 2-(t-Butyl)6-methyl 3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate

A stirred solution of t-butyl6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.0 g, 16.0 mmol, 1.0eq.) in methanol (45 mL) and acetonitrile (10 mL) was treated withPdCl₂(dppf) (0.95 g, 1.28 mmol, 0.08 eq) and TEA (3.23 g, 3.20 mmol, 2.0eq) in an autoclave. The resulting reaction mixture was taken 22 kg/cm²CO(g) pressure and heated to 100° C. for 24 h. The cooled reactionmixture was filtered through a celite bed, washed with ethyl acetate (50mL) and the combined filtrate concentrated under vacuum. The obtainedcrude material was purified by flash chromatography (product eluted by5% ethyl acetate in hexane) yielding the title compound (3.8 g, 13.04mmol. Yield: 81.4%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.43 (s, 9H), 2.85 (t, J=6.0 Hz, 2H), 3.57(t, J=6.0 Hz, 2H), 3.84 (s, 3H), 4.57 (s, 2H), 7.32 (d, J=8.0 Hz, 1H),7.76-7.77 (m, 2H). LCMS (Method A): 2.233 min, MS: ES+192.18 (M+1-100).

2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid

To a stirred solution of 2-(tert-butyl) 6-methyl3,4-dihydroisoquinoline-2,6(1/H)-dicarboxylate (3.8 g, 13.0 mmol, 1.0eq.) in methanol:water (1:1) (20 mL) at room temperature was added NaOH(2.6 g, 65.0 mmol, 5.0 eq.). The resulting reaction mixture was heatedto 70° C. and stirred for 2 h. The resulting mixture was allowed to coolto 0-5° C., acidified using 1 N HCl solution and extracted with ethylacetate (3×30 mL). The combined organic layer was dried over Na₂SO₄,filtered, and distilled under vacuum yielding the title compound as abrown oil (3.5 g, 13.7 mmol, Yield: 97.2%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.43 (s, 9H), 2.84 (t, J=5.6 Hz, 2H), 3.57(t, J=5.6 Hz, 2H), 4.56 (s, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.74-7.75 (m,2H), 12.90 (s, 1H). LCMS (Method A): 1.837 min, MS: ES, 178.17(M+1-100).

tert-butyl6-(dimethylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a stirred solution of2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid(3.5 g, 12.6 mmol, 1.0 eq) in DMF (10 ml) at 0° C.-5° C. were added HATU(7.19 g, 18.9 mmol, 1.5 eq) and DIPEA (3.25 g, 25.4 mmol, 2.0 eq). Thereaction mixture was stirred for 30 mins at 0° C.-5° C. Dimethyl amine(2M in THF) (6.94 mL, 13.88 mmol, 1.1 eq.) was added dropwise at 0-5° C.The resulting reaction was gradually raised to room temperature andstirred for 16 h. Reaction completion was monitored by TLC (ethylacetate: hexane 1:1). The reaction mixture was poured onto ice-coldwater (100 mL), extracted into ethyl acetate (2×50 mL) and the combinedorganic layer washed with cold water (50 mL), dried with Na₂SO₄,filtered and concentrated under vacuum. The crude material was purifiedby flash chromatography (eluting product with 4% methanol in DCM) togive the title compound (3.5 g, 11.49 mmol. Yield: 91.14%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.43 (s, 9H), 2.79 (t, J=6.0 Hz, 2H),2.96-2.99 (singlets, br, 6H), 3.56 (t, J=6.0 Hz, 2H), 4.52 (s, 2H),7.20-7.24 (m, 3H). LCMS (Method A): 1.775 min, MS: ES+249.05 (M−56).

N,N-Dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Intermediate43a)

To a stirred solution of t-butyl 6-(dimethylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.5 g, 11.50 mmol,1.0 eq.) in DCM (4 mL) at 0-5° C. was treated dropwise with TFA (17.5mL). The resulting reaction mixture was stirred at room temperature for2 h. Reaction completion was monitored by TLC (methanol: DCM 9:1). Theresulting reaction was concentrated, and remaining TFA was removed byco-distillation with DCM (2×10 mL) followed by n-pentane (10 mL); thecrude material was dried over high vacuum to give crude material as theTFA salt (3.6 g). Of this material, 1.6 g was taken into DCM (30 mL),cooled to 0-5° C., basified using 1N NaOH solution and extracted withdichloromethane (3×30 mL). The combined organic layer was dried overNa₂SO₄, filtered, and concentrated under reduced pressure to give thetitle compound (0.9 g, 4.40 mmol. Yield: 88.53%).

¹H NMR (DMSO-d6, 400 MHz): δ 2.70 (t, J=5.2 Hz, 2H), 2.91-2.96 (m, 8H),3.87 (s, 2H), 7.04-7.13 (m, 3H). LCMS (Method B): 1.40 min, MS:ES+205.25 (M+1).

N,N-Dimethyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)methanamine(Intermediate 43)

A stirred solution ofN,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Intermediate43a) (0.5 g, 2.44 mmol, 1.0 eq.) in THF (5 mL) at 0-5° C. was treateddropwise with LiAlH₄ (2M in THF) (3.54 mL, 2.9 eq) and stirred for 10mins. The resulting reaction mixture was heated to 75° C. and stirredfor 3 h. Reaction completion was monitored by TLC (DCM: MeOH 4:1). Thereaction mixture was allowed to cool to 0-5° C., basified using 1N NaOHsolution and extracted with dichloromethane (2×20 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the title compound as yellow oil (0.350 g, 1.84mmol, Yield: 75.43%).

¹H NMR (DMSO-d6, 400 MHz): δ 2.09-2.11 (m, 6H), 2.64-2.65 (m, 2H),2.90-2.91 (m, 2H), 3.27-3.29 (m, 2H), 3.78-3.80 (m, 2H), 6.93-6.99 (m,3H). LCMS (Method B): 1.39 min, MS: ES+191.28 (M+1).

Synthesis of 1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (Intermediate44)

Methyl isoquinoline-1-carboxylate

A stirred solution of isoquinoline-1-carboxylic acid (7.0 g, 40.46 mmol,1.0 eq) (CAS: 486-73-7) in MeOH (350 mL) at room temperature was treateddropwise with cH₂SO₄ (15 mL). The reaction mixture was heated to 65° C.and stirred for 5 h. The reaction mixture was carefully poured intosaturated NaHCO₃ (50 mL) and extracted with DCM (500 mL). The aq. layerwas extracted with DCM (200 mL). The combined organic layer was driedover Na₂SO₄, filtered and concentrated under reduced pressure yieldingthe title compound (4.7 g, 25.10 mmol. Yield: 62.16%).

LCMS (Method A): 1.484 min, MS: ES+188.13 (M+1).

Isoquinolin-1-ylmethanol

A stirred solution of methyl isoquinoline-1-carboxylate (4.5 g, 24.03mmol, 1.0 eq) in THF (350 mL) and EtOH (40 mL) at room temperature weretreated with NaBH₄ (1.8 g, 48.07 mmol, 2.0 eq) and LiCl (2.03 g, 48.07,2.0 eq). The reaction mixture was stirred at room temperature for 24 h.The reaction mixture was quenched into ice cold water (200 mL) andextracted with DCM (2×200 mL). The combined organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crude waspurified by flash chromatography (product eluted in 2% MeOH in DCM)yielding the title compound (1.2 g, 7.53 mmol. Yield: 39.16%).

¹H NMR (DMSO-d6, 400 MHz): δ 5.05 (d, J=5.2 Hz, 2H), 5.42 (t, J=5.2 Hz,1H), 7.69 (t, J=7.6 Hz, 1H), 7.76-7.80 (m, 2H), 7.98 (d, J=8 Hz, 1H),8.35 (d, J=8.4 Hz, 1H), 8.42 (d, J=5.6 Hz, 1H). LCMS (Method A): 0.376min, MS: ES+160.12 (M+1).

1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (Intermediate 44)

A stirred solution of isoquinolin-1-ylmethanol (1.0 g, 6.28 mmol, 1.0eq) in MeOH (100 mL) at room temperature in autoclave was treated withPtO₂ monohydrate (0.129 g, 0.56 mmol, 0.09 eq). The resulting reactionmixture was stirred at room temperature for 16 h under 60 psi pressureof H₂ (gas). Reaction completion was monitored by TLC (DCM: MeOH; 9:1).The reaction mixture was filtered through celite bed and concentratedunder reduced pressure yielding the title compound (0.85 g, 5.20 mmol.Yield: 85.0%,).

LCMS (Method B): 1.46 min, MS: ES+164.16 (M+1). The crude material wasused in next step without purification.

Synthesis of (1,2,3,4-tetrahydroisoquinolin-4-yl)methanol (Intermediate45)

Isoquinoline-4-carbaldehyde

A stirred solution of 4-bromoisoquinoline (4.0 g, 19.4 mmol, 1.0 eq)(CAS: 532-97-4) in THF (40 ml) at −78° C. was treated dropwise withn-BuLi (8.5 mL, 21.3 mmol, 1.1 eq), then DMF (2.8 mL, 38.8 mmol, 2.0 eq)was added dropwise; the resulting reaction mixture was stirred at -780Cfor 30 min. The reaction mixture was poured into saturated solution ofNH₄Cl (50 mL) and extracted with diethyl ether (4×25 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated undervacuum. The crude was purified by flash chromatography using neutralalumina; (product eluted in 5% EtOAc in hexane) yielding the titlecompound (1.8 g, 11.46 mmol. Yield: 37.07%).

¹H NMR (DMSO-d6, 400 MHz): δ 7.85 (t, J=7.2 Hz, 1H), 8.01-8.05 (m, 1H),8.32 (d, J=8 Hz, 1H), 9.07-9.10 (m, 2H), 9.61 (s, 1H), 10.42 (s, 1H).LCMS (Method A): 1.369 min, MS: ES+158.0 (M+1).

Isoquinolin-4-ylmethanol

A stirred solution of isoquinoline-4-carbaldehyde (1.8 g, 11.4 mmol, 1.0eq) in EtOH (260 mL at room temperature) was treated with NaBH₄ (0.43 g,11.4 mmol, 1.0 eq) added portionwise. The reaction mixture was stirredat room temperature for 40 min. Water (100 mL) was added to the reactionmixture and stirred for 20 minutes. AcOH (4.1 mL, 68.4 mmol, 6.0 eq) wasadded drop wise to the reaction mixture at room temperature. Thereaction mixture was extracted with DCM (200 mL) and washed withsaturated solution of NaHCO₃ (50 mL). The combined organic layer wasdried by Na₂SO₄, filtered, and concentrated under vacuum. The crude waspurified by flash chromatography (product eluted in 30% EtOAc in hexane)yielding the title compound (0.7 g, 4.39 mmol. Yield: 38.4%).

¹H NMR (DMSO-d6, 400 MHz): δ 4.94 (d, J=5.0 Hz, 2H), 5.40 (t, J=5.2 Hz1H), 7.70 (t, J=7.6 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 8.14 (d, J=8.4 Hz,2H), 8.48 (s, 1H), 9.24 (s, 1H). LCMS (Method A): 0.264 min, MS:ES+160.2 (M+1).

(1,2,3,4-tetrahydroisoquinolin-4-yl)methanol (Intermediate 45)

A stirred solution of isoquinolin-4-ylmethanol (0.5 g, 3.14 mmol, 1.0eq) in MeOH (20 mL) in an autoclave at room temperature was treated withPtO₂ monohydrate (0.064 g, 0.28 mmol, 0.09 eq); 60 psi of H₂(gas) wasapplied and the mixture stirred for 16 h at room temperature. Thereaction mixture was filtered through a small Millipore filter, washedwith MeOH (3×25 mL) and the combined filtrate concentrated under vacuumyielding the tile compound (0.19 g, 1.16 mmol. Yield: 19.7%).

LCMS (Method A): 1.67 min, MS: ES+164.16 (M+1).

Synthesis of 1-(isoindolin-5-yl)N,N-dimethylmethanamine hydrochloride(Intermediate 46) (Reaction Scheme Shown in FIG. 15)t-Butyl-5-(bromomethyl)isoindoline-2-carboxylate

To a stirred solution of t-butyl 5-(hydroxymethyl)isoindoline-2-carboxylate (3.0 g, 12.0 mmol, 1.0 eq) in DCM (30 mL) at0° C. were added PPh₃ (4.73 g, 18.04 mmol, 1.5 eq) and CBr₄ (2.99 g,18.04 mmol, 1.5 eq). The resulting reaction mixture was stirred at roomtemperature for 3 h and then evaporated under reduced pressure. Thecrude material was purified by flash chromatography (product eluted in20% EtOAc/hexane) yielding the title compound (2.7 g, 8.64 mmol. Yield:71.05%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.45 (s, 9H), 4.57 (d, J=8.4 Hz, 4H), 4.72(s, 2H), 7.30-7.41 (m, 3H). LCMS (Method A): 2.278 min. MS: ES+212.1(M−100).

t-Butyl 5-((dimethylamino)methyl)isoindoline-2-carboxylate

A stirred solution of t-butyl 5-(bromomethyl) isoindoline-2-carboxylate(1.5 g, 4.80 mmol, 1.0 eq) in DMF (10 mL) at room temperature wastreated with K₂CO₃ (4.65 g, 33.6 mmol, 7.0 eq) and stirred for 20 min.Dimethylamine. HCl (0.980 g, 12.0 mmol, 2.5 eq) was added to thereaction mixture at room temperature and stirred for 16 h. The resultingreaction mixture was poured onto ice-cold water (100 mL) and extractedinto ethyl acetate (3×30 mL). The combined organic layer was dried overNa₂SO₄, filtered and concentrated under vacuum. The crude material waspurified by flash chromatography (product eluted in 8% ethyl acetate inhexane) to give the title compound (0.550 g, 1.99 mmol. Yield: 41.41%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.53 (s, 9H), 2.90 (s, 3H), 2.98 (s, 3H),4.66-4.70 (m, 4H), 7.21-7.33 (m, 3H). LCMS (Method A): 1.074 min, MS:ES+277.21 (M+1).

1-(isoindolin-5-yl)N,N-dimethylmethanamine hydrochloride (Intermediate46)

A stirred solution of t-butyl5-((dimethylamino)methyl)isoindoline-2-carboxylate (0.55 g, 1.98 mmol,1.0 eq.) in DCM (5 mL) at 0-5° C. was treated with 4M HCl in dioxane (5mL). The resulting reaction mixture stirred at room temperature for 16h. Reaction completion was monitored by TLC (methanol: DCM 9:1). Theresulting reaction mixture was evaporated under reduced pressure and thecrude material was triturating using diethyl ether (5 mL) yielding thetitle compound (0.350 g, 1.98 mmol, Yield: 100%) which was used in nextstep without purification.

LCMS (Method B): 1.28 min, MS: ES+177.13 (M+1).

Synthesis of 4-(isoindolin-5-ylmethyl) morpholine hydrochloride(Intermediate 47)

t-Butyl 5-(morpholinomethyl)isoindoline-2-carboxylate

Conducted as two parallel batches of 0.35 g. A stirred solution oft-butyl 5-formylisoindoline-2-carboxylate (0.35 g, 1.41 mmol, 1.0 eq) inMeOH (5 mL) at room temperature was treated with morpholine (0.12 g,1.41 mmol, 1.0 eq) and ZnCl₂ (0.09 g, 0.70 mmol, 0.5 eq). The resultingreaction mixture was heated to 70° C. and stirred for 6 h. NaCNBH₃ (0.17g, 2.82 mmol, 2.0 eq) was added portionwise to the reaction mixture at0° C. The reaction mixture was stirred at room temperature for 16 h. Thereaction mixture was concentrated under vacuum, the crude material waspoured into water (50 mL) and extracted with ethyl acetate (3×100 mL).The combined organic layer washed with brine solution (2×50 mL), driedover Na₂SO₄, filtered and concentrated under vacuum. The crude materialwas purified by flash chromatography (product eluted in 3% MeOH in DCM)yielding the title compound (0.61 g, 1.91 mmol. Yield: 67.6%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.45 (s, 9H), 2.33-2.34 (m, 4H), 3.45 (s,2H), 3.55-3.57 (m, 4H), 4.48-4.56 (m, 4H), 7.20-7.28 (m, 3H). LCMS(Method A): 1.192 min, MS: ES+319.26 (M+1).

4-(isoindolin-5-ylmethyl) morpholine hydrochloride (Intermediate 47)

To a stirred solution of t-butyl5-(morpholinomethyl)isoindoline-2-carboxylate (0.25 g, 0.78 mmol, 1.0eq) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (2.5 mL) at 0° C. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was concentrated under reduced pressure and the crude materialtriturated using diethyl ether (2×20 mL) to give the title compound(0.26 g, 1.19 mmol, Yield 100%).

¹H NMR (DMSO-d6, 400 MHz): δ 3.06-3.09 (m, 2H), 3.18-3.21 (m, 2H),3.80-3.93 (m, 4H), 4.34-4.35 (m, 2H), 4.52 (s, br, 4H), 7.48 (d, J=8 Hz,1H), 7.63-7.65 (m, 2H), 10.20 (s, 2H)._LCMS (Method A): 1.54 min, MS:ES+219.33 (M+1).

Synthesis of 4-((4-Methylpiperazin-1-yl)methyl) isoindolinehydrochloride (Intermediate 48) (Reaction Scheme Shown in FIG. 16)t-Butyl-4-(hydroxymethyl)isoindoline-2-carboxylate

A stirred solution of 2-(t-butyl)-4-methyl isoindoline-2,4-dicarboxylate (4.0 g, 14.4 mmol, 1.0 eq) in THF (80 mL) at 0° C. wastreated dropwise with LiAlH₄ solution (1.0 M in THF) (14.4 mL, 14.4mmol, 1.0 eq). The resulting reaction mixture was stirred at 0° C. for 1h and carefully poured onto ice cold saturated NH₄Cl in water (50 mL)and extracted with ethyl acetate (3×100 mL). The combined organic layerwas dried over Na₂SO₄, filtered and concentrated under vacuum yieldingthe title compound (3.5 g, 14.05 mmol. Yield: 97.34%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.46 (s, 9H), 4.46-4.48 (m, 2H), 4.56-4.59(m, 4H), 5.16-5.20 (m, 1H), 7.21-7.28 (m, 3H). LCMS (Method A): 1.609min, MS: ES+150.1 (M−100).

t-Butyl 4-formylisoindoline-2-carboxylate

To a stirred solution of t-butyl 4-(hydroxymethyl)isoindoline-2-carboxylate (3.5 g, 14.04 mmol, 1.0 eq) in DCM (70 mL) wasadded MnO₂ (35 g, 10% w/w) at room temperature. The resulting reactionmixture was stirred at room temperature for 16 h, filtered through acelite bed, washed with 10% MeOH in DCM (3×100 mL) and the combinedfiltrate concentrated under vacuum. The crude material was purified byflash chromatography (product eluted with 8% ethyl acetate in n-hexane)to give the title compound (2.0 g, 8.08 mmol. Yield: 57.6%).

¹H NMR (DMSO-d6, 400 MHz): 1.46-1.47 (m, 9H), 4.61 (d, J=10.4 Hz, 2H),4.83 (d, J=8 Hz, 2H), 7.58 (t, J=6.4 Hz, 1H), 7.67 (t, J=5.6 Hz, 1H),7.90 (d, J=6.0 Hz, 1H), 10.06 (d, J=5.6 Hz, 1H). LCMS (Method A): 1.993min, MS: ES+192.1 (M−56).

t-Butyl-4-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate

Three batches of 0.3 g scale progressed in parallel. A stirred solutionof t-butyl 4-formylisoindoline-2-carboxylate (0.3 g, 1.21 mmol, 1.0 eq)in MeOH (10 mL) at room temperature was treated with N-methyl piperazine(0.121 g, 1.21 mmol, 1.0 eq) and ZnCl₂ (0.078 g, 0.60 mmol, 0.5 eq). Thereaction mixture was heated to 70° C. and stirred for 16 h. NaCNBH₃(0.152 g, 2.42 mmol, 2.0 eq) was added portionwise to the reactionmixture at 0° C. The resulting reaction mixture was stirred at roomtemperature for 16 h. The reaction mixture was concentrated undervacuum, poured into water (50 mL) and extracted with ethyl acetate(3×100 mL). The combined organic layer was washed by brine solution (30mL), dried with Na₂SO₄, filtered and concentrated under vacuum. Thecrude material was purified by flash chromatography (product eluted with4% MeOH in DCM) to give the title compound (0.6 g, 1.80 mmol. Yield49.7%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.46 (s, 9H), 2.61-2.63 (m, 5H), 2.95-2.97(m, br, 4H), 3.34-3.35 (m, br, 4H), 4.57-4.63 (m, 4H), 7.19-7.25 (m,3H). LCMS (Method A): 1.212 min, MS: ES+332.37 (M+1).

4-((4-Methylpiperazin-1-yl)methyl) isoindoline hydrochloride(Intermediate 48)

To a stirred solution of t-butyl 4-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate (0.3 g, 0.9 mmol, 1.0 eq) in DCM (2 mL)was added 4M HCl in dioxane (1 mL) at 0° C. The resulting reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas concentrated under vacuum yielding the title compound which was useddirectly in the next step (0.3 g, Yield: quantitative, 1.29 mmol).

LCMS (Method A): 0.165 min, MS: ES+232.19 (M+1).

Synthesis of 4-(isoindolin-4-ylmethyl)morpholine hydrochloride(Intermediate 49)

t-Butyl 4-(morpholinomethyl)isoindoline-2-carboxylate

2 Batches of 0.4 g scale were progressed in parallel. A stirred solutionof t-butyl 4-formylisoindoline-2-carboxylate (0.4 g, 1.62 mmol, 1.0 eq)in MeOH (5 mL) at room temperature were treated with morpholine (0.169g, 1.94 mmol, 1.2 eq) and ZnCl₂ (0.110 g, 0.810 mmol, 0.5 eq). Thereaction mixture was heated to 70° C. and stirred for 16 h. NaCNBH₃(0.203 g, 3.23 mmol, 2.0 eq) was added portion wise to the reactionmixture at 0° C. The reaction mixture was stirred at room temperaturefor 2 h. The reaction mixture was concentrated under vacuum and thecrude material purified by flash chromatography (product eluted with 30%ethyl acetate in hexane) to give the title compound (0.6 g, 1.89 mmol.Yield: 58.25%).

¹H NMR (DMSO-d6, 400 MHz): δ ppm 1.45-1.46 (m, 9H), 2.33 (m, br, 4H),3.43 (s, 2H), 3.55-3.56 (m, 4H), 4.56-4.64 (m, 4H), 7.18-7.24 (m, 3H).LCMS (Method A): 1.221 min, MS: ES+319.2 (M+1).

4-(isoindolin-4-ylmethyl)morpholine hydrochloride (Intermediate 49)

A stirred solution of t-butyl4-(morpholinomethyl)isoindoline-2-carboxylate (0.6 g, 1.89 mmol, 1.0 eq)in DCM (5 mL) was cooled to 0° C. and 4M HCl in dioxane (6 mL) was addeddropwise. The reaction mixture was stirred at room temperature for 1 h.The reaction mixture was concentrated under vacuum and the crudematerial triturated using n-pentane (3×10 mL) followed by diethyl ether(10 mL) and dried under high vacuum yielding to give the title compoundas a pink solid (0.6 g, 2.36 mmol. Yield 100%).

¹H NMR (DMSO-d6, 400 MHz): δ 3.16-3.27 (m, 4H), 3.85-3.93 (m, 4H),4.34-4.35 (m, 2H), 4.51-4.54 (m, 2H), 4.81-4.84 (m, 2H), 7.44-7.51 (m,2H), 7.68-7.70 (m, 1H), 10.2 (s, 2H). LCMS (Method B): 1.65 min, MS:ES+219.03 (M+1).

Synthesis of N-(tetrahydrofuran-3-yl)isoindolin-4-amine hydrochloridesalt (Intermediate 50)

t-Butyl 4-((tetrahydrofuran-3-yl) amino) isoindoline-2-carboxylate

t-Butyl 4-bromoisoindoline-2-carboxylate (1.00 g, 3.36 mmol, 1 eq),tetrahydrofuran-3-amine hydrochloride (0.624 g, 5 mmol, 1.5 eq) and 1,4-dioxane (5 mL) were placed in a 35 mL microwave glass tube and themixture degassed at room temperature using N₂ gas for 30 min. NaOtBu(0.805 g, 8.38 mmol, 2.5 eq) and Brettphos (0.108 g, 0.20 mmol, 0.06 eq)were added to reaction mixture and again purged with N₂ for 10 min.Pd₂(dba)₃ (0.092 g, 0.10 mmol, 0.03 eq) was added and the reactionheated to 110° C. under microwave irradiation for 1.5 h. The reactionmixture was filtered through celite and washed with ethyl acetate (2×50mL). The combined filtrate was poured to ice-cold water (100 mL) andextracted in ethyl acetate (3×100 mL). The combined organic layer wasdried over Na₂SO₄, filtered, and concentrated under vacuum. The crudematerial was purified by flash chromatography (product eluted in 20%EtOAc in hexane) to give the title compound as a yellow solid (0.6 g,Yield: 58.82%, 1.97 mmol).

¹H NMR (DMSO-d6, 400 MHz): δ ppm 1.47 (s, 9H), 1.83-1.86 (m, 1H),2.13-2.19 (m, 1H), 3.55-3.59 (m, 1H), 3.69-3.74 (m, 1H), 3.79-3.85 (m,1H), 3.88-3.92 (m, 1H), 4.01-4.02 (m, 1H), 4.42 (d, J=4.4 Hz, 2H),4.49-4.52 (m, 2H), 5.34-5.39 (m, 1H, D₂O exchangeable), 6.42-6.45 (m,1H), 6.53-6.57 (m, 1H), 7.06-7.10 (m, 1H). LCMS (Method A): 2.038 min,MS: ES+249.15 (M−56).

N-(tetrahydrofuran-3-yl)isoindolin-4-amine hydrochloride salt(Intermediate 50)

A stirred solution of t-butyl 4-((tetrahydrofuran-3-yl) amino)isoindoline-2-carboxylate (0.550 g, 1.81 mmol, 1.0 eq) in DCM (5 mL) at0° C. was treated dropwise with 4M HCl in dioxane (0.5 mL). The reactionmixture was stirred for 1 h at RT. The reaction mixture was concentratedunder vacuum and crude material triturated using n-pentane (3×10 mL)followed by diethyl ether (10 mL) to give solid that was dried underhigh vacuum to give the title compound (0.50 g, 2.08 mmol. Yield 100%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.82-1.84 (m, 1H), 2.15-2.24 (m, 1H),3.57-3.60 (m, 2H), 3.69-3.74 (m, 1H), 3.81-3.92 (m, 2H), 4.30-4.33 (m,2H), 4.35-4.40 (m, 2H), 6.54 (d, J=8.0 Hz, 1H), 6.64 (d, J=7.6 Hz, 1H),7.16 (t, J=8 Hz, 15.6 Hz, 1H). LCMS (Method A): 0.702 min. MS: ES+205.18(M+1).

Synthesis of N-(Oxetan-3-yl)isoindolin-4-amine·TFA salt (Intermediate51)

t-Butyl 4-(oxetan-3-ylamino) isoindoline-2-carboxylate

A mixture of tert-butyl 4-bromoisoindoline-2-carboxylate (1.00 g, 3.36mmol, 1 eq) and oxetan-3-amine (0.735 g, 6.71 mmol, 2 eq) in 1,4-dioxane (5 mL) at room temperature in a 35 mL microwave glass vial wastreated with NaOtBu (0.451 g, 4.70 mmol, 1.4 eq) and the mixturedegassed using N₂ gas for 10 min. BINAP (0.125 g, 0.20 mmol, 0.06 eq)and Pd₂(dba)₃ (0.120 g, 0.13 mmol, 0.04 eq) were added and again purgedwith N₂ for 10 min. The reaction resulting reaction mixture was heatedto 130° C. under microwave irradiation for 1.5 h. The reaction mixturewas filtered through celite, washed with ethyl acetate (2×50 mL) and thecombined filtrate poured onto ice-cold water (100 mL) and extracted inethyl acetate (3×100 mL). The combined organic layer was dried overNa₂SO₄, filtered, and concentrated under vacuum. The crude material waspurified by flash chromatography (product eluted in 20% EtOAc in hexane)yielding the title compound as a yellow solid (0.8 g, 2.76 mmol. Yield:78.16%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.47 (2 singlets, 9H), 4.44-4.58 (m, 7H),4.83 (t, J=6 Hz, 12 Hz, 2H), 5.99-6.02 (m, 1H), 6.16-6.18 (m, 1H), 6.59(t, J=7.6 Hz, 14.8 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H). LCMS (Method A):2.051 min, MS: ES+235.1 (M−56).

N-(Oxetan-3-yl)isoindolin-4-amine·TFA salt (Intermediate 51)

A stirred solution of t-butyl 4-((tetrahydrofuran-3-yl) amino)isoindoline-2-carboxylate (0.4 g, 1.32 mmol, 1.0 eq) in DCM (5 mL) at 0°C. was treated dropwise with 4M HCl in dioxane (1.5 mL). The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas concentrated under vacuum and the crude material triturated usingn-pentane (3×10 mL) followed by diethyl ether (10 mL) and dried underhigh vacuum to give the title compound (0.4 g, 1.2 mmol. Yield: 91%).

¹H NMR (DMSO-d6, 400 MHz): δ 4.30-4.47 (m, 6H), 4.52-4.61 (m, 1H), 4.83(t, J=6.4 Hz, 2H), 6.26 (d, J=8 Hz, 1H), 6.66 (d, J=8 Hz, 1H), 7.16 (t,J=8 Hz, 1H). 9.42 (m, 3H) LCMS (Method A): 0.735 min, MS: ES+191.2(M+1).

Synthesis of 1-(isoindolin-4-yl)piperidin-3-ol hydrochloride(Intermediate 52)

t-butyl 4-(3-hydroxypiperidin-1-yl)isoindoline-2-carboxylate

t-Butyl 4-bromoisoindoline-2-carboxylate (1.00 g, 3.36 mmol, 1 eq),piperidin-3-ol (0.670 g, 6.63 mmol, 2 eq) and NaOtBu (0.451 g, 4.70mmol, 1.4 eq) in 1,4-dioxane (5 mL) were added to a 35 mL microwaveglass tube. The reaction mixture was degassed using N₂ gas for 10 min.BINAP (0.125 g, 0.20 mmol, 0.06 eq) and Pd₂(dba)₃ (0.120 g, 0.13 mmol,0.04 eq) were added to the reaction mixture which was again purged withN₂ for 10 min. The reaction was heated to 130° C. under microwaveirradiation for 1.5 h. The reaction mixture was filtered through acelite bed and washed with ethyl acetate (2×50 mL). The combinedfiltrate was poured to ice cold water (100 mL) and extracted in ethylacetate (3×100 mL). The combined organic layer was dried over Na₂SO₄,filtered, and concentrated under vacuum. The crude material was purifiedby flash chromatography (product eluted in 20% EtOAc in hexane) yieldingthe title compound as a yellow solid (0.6 g, Yield: 56.23%, 1.89 mmol).

¹H NMR (DMSO-d6, 400 MHz): δ ppm 1.24 (m, 1H), 1.46 (s, 9H), 1.5 (m,1H), 1.74 (m, 1H), 1.99 (m, 1H), 3.06 (m, 2H), 3.17-3.23 (m, 2H), 3.59(m, 1H), 4.52-4.56 (m, 3H), 4.81-4.84 (m, 1H), 6.84 (t, J=7.6 Hz, 15.6Hz, 1H), 6.93 (t, J=8 Hz, 16.8 Hz, 1H), 7.20-7.22 (m, 1H). LCMS (MethodA): 1.929 min, MS: ES+319.3 (M+1).

1-(isoindolin-4-yl)piperidin-3-ol hydrochloride (Intermediate 52)

A stirred solution of t-butyl4-(3-hydroxypiperidin-1-yl)isoindoline-2-carboxylate (0.5 g, 1.57 mmol,1.0 eq) in DCM (5 mL) at 0° C. was treated dropwise with 4M HCl indioxane (5 mL). The reaction mixture was stirred at room temperature for1 h. The reaction mixture was concentrated under vacuum and the crudematerial triturated using n-pentane (3×10 mL) followed by diethyl ether(10 mL) and dried under high vacuum yielding the title compound as brownsolid (0.500 g, 1.97 mmol, Yield 100%).

¹H NMR (DMSO-d6, 400 MHz): δ 1.24-1.35 (m, 1H), 1.60-1.63 (m, 1H),1.80-1.90 (m, 2H), 2.55-2.60 (m, 1H), 2.68-2.74 (m, 1H), 3.09-3.12 (m,1H), 3.18-3.21 (m, 1H), 3.71 (bs, 1H), 4.46 (s, br, 4H), 6.99-7.01 (m,1H), 7.05-7.07 (m, 1H), 7.33 (t, J=7.6 Hz, 15.6 Hz, 1H), 9.98 (s, 2H).LCMS (Method A): 0.555 min, MS ES+219.2 (M+1).

Synthesis of 5-((4-methylpiperazin-1-yl) methyl) isoindoline. HCl salt(Intermediate 53)

t-Butyl 5-((4-methylpiperazin-1-yl) methyl) isoindoline-2-carboxylate

A stirred solution of t-butyl 5-formylisoindoline-2-carboxylate (4.0 g,16.17 mmol, 1.0 eq) in MeOH (100 mL) at room temperature was treatedwith N-methyl piperazine (1.61 g, 16.17 mmol, 1.0 eq) and ZnCl₂ (1.04 g,8.05 mmol, 0.5 eq). The reaction mixture was heated to 70° C. andstirred for 16 h. The resulting reaction mixture was allowed to cool to0° C. and treated with NaCNBH₃ (2.02 g, 32.2 mmol, 2.0 eq). Theresulting reaction mixture was stirred at room temperature for 16 h. Thereaction mixture was concentrated under vacuum, water (100 mL) was addedand extracted using ethyl acetate (3×150 mL). The combined organic layerwas dried over Na₂SO₄, filtered, and concentrated under vacuum. Thecrude material was purified by flash chromatography (product was elutedat 6% MeOH in DCM) yielding the title compound (4.3 g, Yield: 80.21%,12.98 mmol).

¹H NMR (DMSO-d6) (400 MHz): 1.45 (s, 9H), 2.23 (s, 3H), 2.40-2.50 (m,8H) (piperazine proton merged), 2.45 (s, 2H), 4.54-4.56 (m, 4H),7.19-7.26 (m, 3H). LCMS (Method A): 0.945 min, MS: ES+332.32 (M+1).

5-((4-methylpiperazin-1-yl) methyl) isoindoline. HCl salt (Intermediate53)

A stirred solution of t-butyl5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate (1.3 g, 3.92mmol, 1.0 eq) in DCM (5 mL) at 0° C. was treated dropwise with 4M HCl indioxane (1 mL). The reaction mixture was stirred at room temperature for2 h. The reaction mixture was concentrated under vacuum yielding thetitle compound (1.3 g, Yield: quantitative, 5.62 mmol).

¹H NMR (DMSO-d6, 400 MHz): 2.78 (s, 3H), 3.20-3.59 (m, br, 4H),3.82-3.84 (m, br, 4H), 4.32-4.35 (m, 2H), 4.51 (s, br, 4H), 7.48 (d,J=7.6 Hz, 1H), 7.64 (s, 2H), 10.15 (s, 1H). LCMS (Method B): 1.33 min,MS: ES+232.37 (M+1).

Biological Assays Fluorescence Polarisation Assay for MLH1 (Protocol forall Examples Except Examples 64, 76, 90 and 95)

Test compounds, as 10 mM DMSO stocks, were dispensed into a BlackFluotrac 200 384 well medium binding plate (Greiner Bio-One, item number781076) using a Labcyte Echo acoustic liquid handler. For single pointscreening, test compounds were added to wells in columns 1-22 whilstDMSO was added to wells in columns 23 and 24 in order to normalise theplate. For potency determination, serial dilutions of test compoundswere added to wells in columns 3-22 and DMSO volume was normalisedacross the plate.

20 μL of a 2× solution (200 nM) of recombinant N-terminal MLH1 (residues15-340) in assay buffer (25 mM HEPES, pH 7.5, 250 mM NaCl, 10 mM MgCl₂,0.01% Triton X-100, 5 mM Dithiothreitol) was added to all wells incolumns 2-23 for potency determination or columns 1-23 for single pointscreening. 20 μL assay buffer was added to all wells in columns 1 and 24(column 24 only for single point screening) using a MultiDrop Combi(ThermoFisher). Plates were centrifuged for 1 minute at 250×g and wereincubated at room temperature for 30 minutes prior to the addition of 20μL of 2×(10 nM) of5-((5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)carbamoyl)-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate(referred to hereinafter as “probe compound”) in assay buffer (preparedfrom a 100 μM DMSO stock) with a MultiDrop Combi (ThermoFisher). Thefinal concentration of N-terminal MLH1 was 100 nM and the finalconcentration of probe compound was 5 nM.

Compound plates were centrifuged for 1 minute at 250×g for 1 minute andwere incubated at room temperature for 15 minutes before being read on aPheraStar FSX (fitted with 384-well aperture spoon and 540 590 590 FPoptic module). The gain and focus were adjusted before each plate wasread so that the polarisation of a no enzyme control (column 24) wasequal to 35 mP. Data were normalised against the no inhibitor controls(column 23) and no enzyme controls (column 24).

Fluorescence Polarisation Assay for MLH1 (Protocol for Examples 64, 76,90 and 95)

Test compounds, as 10 mM DMSO stocks, were dispensed into a 384-well LowFlange Black Flat Bottom Polystyrene Non-binding Surface plate(Corning®, item number 3575) using a Labcyte Echo acoustic liquidhandler. Test compounds were added to wells in columns 1-22 whilst DMSOwas added to wells in columns 23 and 24 in order to normalise the plate.20 μL of a 2× solution (200 nM) of recombinant N-terminal MLH1 (residues15-340) in assay buffer (25 mM HEPES, pH 7.5, 250 mM NaCl, 10 mM MgCl₂,0.01% Triton X-100, 5 mM dithiothreitol) was added to all wells incolumns 1-23 and 20 μL assay buffer was added to all wells in column 24using an E1-ClipTip pipette (ThermoFisher). Plates were centrifuged for1 minute at 250×g and were incubated at room temperature for 30 minutesprior to the addition of 20 μL of 2×(10 nM)5-((5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)carbamoyl)-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoatein assay buffer (prepared from a 1 mM DMSO stock) with an E1-ClipTippipette (ThermoFisher). The final concentration of N-terminal MLH1 was100 nM and the final concentration of the probe compound was 5 nM.Compound plates were centrifuged for 1 minute at 250 xg for 1 minute andimmediately read on a PheraStar FSX (fitted with 384-well aperture spoonand 590 675 675 FP optic module). The gain and focus were adjustedbefore each plate was read so that the polarisation of a no enzymecontrol (column 24) was equal to 35 mP. Data were normalised against theno inhibitor controls (column 23) and no enzyme controls (column 24).

Data obtained in this assay is shown in Table B1 below.

Fluorescence Polarisation Assay for PMS2

Test compounds, as 10 mM DMSO stocks, were dispensed into a BlackFluotrac 200 384 well medium binding plate (Greiner Bio-One, item number781076) using a Labcyte Echo acoustic liquid handler. For single pointscreening, test compounds were added to wells in columns 1-22 whilstDMSO was added to wells in columns 23 and 24 in order to normalise theplate. For potency determination, serial dilutions of test compoundswere added to wells in columns 3-22 and DMSO volume was normalisedacross the plate.

20 μL of a 2× solution (20 nM) of recombinant N-terminal PMS2 (residues1-365) in assay buffer (25 mM HEPES, pH 7.5, 250 mM NaCl, 10 mM MgCl₂,0.01% Triton X-100, 5 mM Dithiothreitol) was added to all wells incolumns 2-23 for potency determination or columns 1-23 for single pointscreening. 20 μL assay buffer was added to all wells in columns 1 and 24(column 24 only for single point screening) using a MultiDrop Combi(ThermoFisher). Plates were centrifuged for 1 minute at 250×g and wereincubated at room temperature for 30 minutes prior to the addition of 20μL of 2×(20 nM) of5-((5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentyl)carbamoyl)-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate(referred to hereinafter as “probe compound”) in assay buffer (preparedfrom a 100 μM DMSO stock) with a MultiDrop Combi (ThermoFisher). Thefinal concentration of N-terminal PMS2 was 10 nM and the finalconcentration of probe compound was 5 nM.

Compound plates were centrifuged for 1 minute at 250×g for 1 minute andwere incubated at room temperature for 1 hour before being read on aPheraStar FSX (fitted with 384-well aperture spoon and 540 590 590 FPoptic module). The gain and focus were adjusted before each plate wasread so that the polarisation of a no enzyme control (column 24) wasequal to 35 mP. Data were normalised against the no inhibitor controls(column 23) and no enzyme controls (column 24).

Data obtained in this assay is shown in Table B1 below.

TABLE B1 *>10 μM **1-10 μM ***less than 1 μM Example Name MLH1 IC₅₀ PMS2IC₅₀ 1 [2,4-dihydroxy-6-(pyrimidin-2- * *ylmethoxy)phenyl]-pyrrolidin-1-yl- methanone 2[2-(cyclopentoxy)-4,6-dihydroxy- * * phenyl]-pyrrolidin-1-yl-methanone 3(2-benzyloxy-4,6-dihydroxy-phenyl)- * * pyrrolidin-1-yl-methanone 4(2-benzyloxy-4,6-dihydroxy-phenyl)- *** *** isoindolin-2-yl-methanone 5(2-benzyloxy-4,6-dihydroxy-phenyl)- * * (1-piperidyl)methanone 6(2-benzyloxy-4,6-dihydroxy-phenyl)- * * [(3S)-3-hydroxypyrrolidin-1-yl]methanone 7 (2-benzyloxy-4,6-dihydroxy-phenyl)- * *[(3R)-3-hydroxypyrrolidin-1- yl]methanone 8(2-benzyloxy-4,6-dihydroxy-phenyl)- * * [(3R)-3-hydroxy-1-piperidyl]methanone 9 (2-benzyloxy-4,6-dihydroxy-phenyl)- * *[(3S)-3-hydroxy-1- piperidyl]methanone 10(2-benzyloxy-4,6-dihydroxy-3-methyl- * **phenyl)-pyrrolidin-1-yl-methanone 11(2-benzyloxy-3-ethyl-4,6-dihydroxy- * *phenyl)-pyrrolidin-1-yl-methanone 12 [2,4-dihydroxy-6-(2- * *pyridylmethoxy)phenyl]-pyrrolidin-1- yl-methanone 13[2,4-dihydroxy-6-[(1R)-1- * * phenylethoxy]phenyl]-pyrrolidin-1-yl-methanone 14 [2,4-dihydroxy-6-[(1R)-1- * *phenylethoxy]phenyl]-pyrrolidin-1-yl- methanone 15[2-[(4-fluorophenyl)methoxy]-4,6- * * dihydroxy-phenyl]-pyrrolidin-1-yl-16 [2,4-dihydroxy-6-[(4- * * methoxyphenyl)methoxy]phenyl]-pyrrolidin-1-yl-methanone 17 [2,4-dihydroxy-6-(m- * *tolylmethoxy)phenyl]-pyrrolidin-1-yl- methanone 18(2-benzyloxy-4,6-dihydroxy-phenyl)- ** **(5,7-dihydropyrrolo[3,4-b]pyridin-6- yl)methanone 19(2-benzyloxy-4,6-dihydroxy-phenyl)- *** ***(4-methoxyisoindolin-2-yl)methanone 20[2,4-dihydroxy-6-(pyrimidin-4- * * ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone 21 2,4-dihydroxy-6-(1H-pyrazol-3- * *ylmethoxy)phenyl]-pyrrolidin-1-yl- methanone 22[2,4-dihydroxy-6-(1H-triazol-4- * * ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone 23 (2-benzyloxy-4,6-dihydroxy-phenyl)- *** ***(5-bromoisoindolin-2-yl)methanone 24 methyl2-(2-benzyloxy-4,6-dihydroxy- *** *** benzoyl)isoindoline-5-carboxylate25 (2-benzyloxy-4,6-dihydroxy-phenyl)- *** ***(5-methoxyisoindolin-2-yl)methanone 26(2-benzyloxy-4,6-dihydroxy-phenyl)- ** *** (5,6-dimethoxyisoindolin-2-yl)methanone 27 [2,4-dihydroxy-6-(1- ** ***phenylethoxy)phenyl]-isoindolin-2-yl- methanone 28 [2,4-dihydroxy-6-(1-** *** phenylethoxy)phenyl]-(5- methoxyisoindolin-2-yl)methanone 29[2,4-dihydroxy-6-(1- ** *** phenylethoxy)phenyl]-(5,6-dimethoxyisoindolin-2-yl)methanone 30(2-benzyloxy-4,6-dihydroxy-3-methyl- * ***phenyl)-(5,7-dihydropyrrolo[3,4- b]pyridin-6-yl)methanone 315,7-dihydropyrrolo[3,4-b]pyridin-6-yl- * ***[4,6-dihydroxy-3-methyl-2-(m- tolylmethoxy)phenyl]methanone 325,7-dihydropyrrolo[3,4-b]pyridin-6-yl- ** *** [2,4-dihydroxy-6-(m-tolylmethoxy)phenyl]methanone 335,7-dihydropyrrolo[3,4-b]pyridin-6-yl- * **[4,6-dihydroxy-3-methyl-2-(2- pyridylmethoxy)phenyl] methanone 34[4,6-dihydroxy-3-methyl-2-(2- * ** pyridylmethoxy)phenyl]-isoindolin-2-yl-methanone 35 5,7-dihydropyrrolo[3,4-b]pyridin-6-yl- ** **[2,4-dihydroxy-6-(2- pyridylmethoxy)phenyl]methanone 36(2-benzyloxy-4,6-dihydroxy-3-methyl- * ***phenyl)-(3,4-dihydro-1H-isoquinolin- 2-yl)methanone 37[2,4-dihydroxy-6-(2- ** ** pyridylmethoxy)phenyl]-isoindolin-2-yl-methanone 38 (2-benzyloxy-4,6-dihydroxy-3-methyl- * ***phenyl)-(4-bromoisoindolin-2- yl)methanone 39(2-benzyloxy-4,6-dihydroxy-3-methyl- * ***phenyl)-[4-(hydroxymethyl)isoindolin- 2-yl]methanone 40(2-benzyloxy-4,6-dihydroxy-3-methyl- * ***phenyl)-[5-[(4-methylpiperazin-1- yl)methyl]isoindolin-2-yl]methanone 41(2-benzyloxy-4,6-dihydroxy-3-methyl- * ***phenyl)-(6-methoxy-3,4-dihydro-1H- isoquinolin-2-yl)methanone 42(2-benzyloxy-4,6-dihydroxy-3-methyl- * ** phenyl)-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)methanone 43 (2-benzyloxy-4,6-dihydroxy-3-methyl- * **phenyl)-(3,4-dihydro-1H-2,6- naphthyridin-2-yl)methanone 443,4-dihydro-1H-isoquinolin-2-yl-[4,6- * *** dihydroxy-3-methyl-2-(m-tolylmethoxy)phenyl]methanone 453,4-dihydro-1H-isoquinolin-2-yl-[4,6- * * dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl] methanone 46 [4,6-dihydroxy-3-methyl-2-(2- * *pyridylmethoxy)phenyl]-(7-methoxy- 3,4-dihydro-1H-isoquinolin-2-yl)methanone 47 [4,6-dihydroxy-3-methyl-2-(2- * *pyridylmethoxy)phenyl]-(6-methoxy- 3,4-dihydro-1H-isoquinolin-2-yl)methanone 48 3,4-dihydro-1H-isoquinolin-2-yl-[2-[(4- * ***fluorophenyl)methoxy]-4,6-dihydroxy- 3-methyl-phenyl]methanone 49(2-(benzyloxy)-4,6- ** *** dihydroxyphenyl)(5-((4- methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone 50 (4-aminoisoindolin-2-yl)(2- * ***(benzyloxy)-4,6-dihydroxy-3- methylphenyl)methanone 51(2-(benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(4-vinylisoindolin-2-yl)methanone 52 (2-(benzyloxy)-4,6-dihydroxy-3- * ***methylphenyl)(7-methoxy-3,4- dihydroisoquinolin-2(1H)- yl)methanone 53(2-(benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methanone 54 (2-(benzyloxy)-4,6-dihydroxy-3- * **methylphenyl)(7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone 55(2-(benzyloxy)-4,6-dihydroxy-3- * **methylphenyl)(7,8-dihydropyrido[4,3- d]pyrimidin-6(5H)-yl)methanone 56(2-(benzyloxy)-4,6-dihydroxy-3- * **methylphenyl)(5,8-dihydropyrido[3,4- d]pyrimidin-7(6H)-yl)methanone 57(3,4-dihydroisoquinolin-2(1H)-yl)(4,6- * *dihydroxy-3-methyl-2-((1-methyl-1H- pyrazol-3- yl)methoxy)phenyl)methanone 58 (2-(benzyloxy)-4,6- ** ** dihydroxyphenyl)(3,4-dihydroisoquinolin-2(1H)- yl)methanone 59(2-(benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(isoindolin-2-yl)methanone 60 (2-(benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(7-((dimethylamino)methyl)-3,4- dihydroisoquinolin-2(1H)- yl)methanone 61(2-(benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(6-((dimethylamino)methyl)-3,4- dihydroisoquinolin-2(1H)- yl)methanone 62(S)-(2-(Benzyloxy)-4,6-dihydroxy-3- * **methylphenyl)(3-(hydroxymethyl)-3,4- dihydroisoquinolin-2(1H)-yl)methanone 63 (2-(benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(1-(hydroxymethyl)isoindolin-2- yl)methanone 64(R)-(2-(benzyloxy)-4,6-dihydroxy-3- * **methylphenyl)(3-(hydroxymethyl)-3,4- dihydroisoquinolin-2(1H)-yl)methanone 65 (2-(Benzyloxy)-4,6-dihydroxy-3- * *methylphenyl)(1-(hydroxymethyl)-3,4- dihydroisoquinolin-2(1H)-yl)methanone 66 (2-(Benzyloxy)-4,6-dihydroxy-3- * **methylphenyl)(4-(hydroxymethyl)-3,4- dihydroisoquinolin-2(1H)-yl)methanone 67 (2-(Benzyloxy)-4,6-dihydroxy-3- * *methylphenyl)(2,3-dihydro-4/7- benzo[b][1,4]oxazin-4-yl)methanone 68(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(5-((dimethylamino)methyl)isoindolin-2- yl)methanone 69(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(5-(morpholinomethyl)isoindolin-2- yl)methanone 70(2-(Benzyloxy)-4,6-dihydroxy-3- * **methylphenyl)(indolin-1-yl)methanone 71 (2-(Benzyloxy)-4,6- ** **dihydroxyphenyl)(indolin-1- yl)methanone 72(2-(Benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(3,4-dihydroquinolin-1(2H)-yl)methanone 73 (2-(Benzyloxy)-4,6- ** **dihydroxyphenyl)(3,4-dihydroquinolin- 1(2H)-yl)methanone 74(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methanone 75(2-(Benzyloxy)-4,6-dihydroxy-3- * ***methylphenyl)(4-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone 76(2-(Benzyloxy)-4,6-dihydroxy-3- * ** methylphenyl)(4-(morpholinomethyl)isoindolin-2- yl)methanone 772-(2-(Benzyloxy)-4,6-dihydroxy-3- * ***methylbenzoyl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide 782-(2-(benzyloxy)-4,6-dihydroxy-3- * ***methylbenzoyl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxamide 79(2-(Benzyloxy)-4,6-dihydroxy-3- * ***methylphenyl)(4-((tetrahydrofuran-3- yl)amino)isoindolin-2-yl)methanone80 (2-(Benzyloxy)-4,6-dihydroxy-3- ** *** methylphenyl)(4-(oxetan-3-ylamino)isoindolin-2-yl)methanone 81 (2-(Benzyloxy)-4,6-dihydroxy-3- **** methylphenyl)(4-(3-hydroxypiperidin- 1-yl)isoindolin-2-yl)methanone82 2-(2-(benzyloxy)-4,6-dihydroxy-3- * *** methylbenzoyl)isoindoline-4-carbonitrile 83 2-(2-(Benzyloxy)-4,6-dihydroxy-3- * ***methylbenzoyl)-N,N- dimethylisoindoline-5-carboxamide 842-(2-(Benzyloxy)-4,6-dihydroxy-3- * ***methylbenzoyl)-N-methylisoindoline- 5-carboxamide 852-(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide 86 2-(2-(Benzyloxy)-4,6-dihydroxy-3- *** methylbenzoyl)-N-methylisoindoline- 4-carboxamide 87N-(2-(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylbenzoyl)isoindolin-4-yl)acetamide 88 ((2-(Benzyloxy)-4,6-dihydroxy-3- * ***methylphenyl)(4-((tetrahydrofuran-3- yl)oxy)isoindolin-2-yl)methanone 89(4-(Azetidin-3-yl methoxy) isoindolin- * *** 2-yl)(2-(benzyloxy)-4,6-dihydroxy- 3-methylphenyl)methanone 90(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone 911-(2-(2-(Benzyloxy)-4,6-dihydroxy-3- * *** methylbenzoyl)isoindolin-4-yl)azetidine-3-carbonitrile 92 (4,6-Dihydroxy-2-methoxy-3- * ***methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone 93 (2-Ethoxy-4,6-dihydroxy-3- **** methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone 94 (2-(Cyclohexylmethoxy)-4,6- **** dihydroxy-3-methylphenyl)(5-((4- methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone 95 (2-(Cyclopropylmethoxy)-4,6- **** dihydroxy-3-methylphenyl)(5-((4- methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone

1. A compound, or pharmaceutically acceptable salts, hydrates orsolvates thereof, having the structural Formula (I), shown below:

wherein R¹ and R³ are independently selected from the group consistingof hydrogen, hydroxy, halogen and (1-4C)alkoxy, with the proviso that atleast one of R¹ and R³ is hydroxy; R² is hydrogen or fluoro; R⁴ isselected from the group consisting of hydrogen, halogen, (1-6C)alkyl,(3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl, wherein the said(1-6C)alkyl is optionally substituted by one or more R^(5a) and the said(3-6C)cycloalkyl and (3-6C)cycloalkyl(1-2C)alkyl groups are optionallysubstituted with one or more R^(5b); where each R^(5a) is independentlyselected from halogen or (1-4C)alkoxy and each R^(5b) is independentlyselected from the group consisting of halogen, (1-4C)alkyl and(1-4C)alkoxy; R⁶ is (1-6C)alkyl, (3-8C)cycloalkyl,(3-8C)cycloalkyl(1-2C)alkyl or a 4- to 7-membered heterocyclyl ringcomprising one heteroatom selected from N, O or S, or a group having astructure according to formula (A) shown below:

wherein R⁷ is hydrogen or (1-3C)alkyl; n is 1 or 2; R⁸ is aryl orheteroaryl, wherein the said aryl or heteroaryl is optionallysubstituted with one or more R⁹; where each R⁹ is independently selectedfrom the group consisting of hydroxy, cyano, halogen, (1-3C)alkyl,(1-3C)alkoxy, (2-3C)alkenyl or (2-3C)alkynyl; R¹⁰ is —NR¹¹R¹², whereinR¹¹ and R¹² are linked, such that, together with the nitrogen atom towhich they are attached, they form a 5-7 membered monocyclicheterocyclic ring that is fused to either a 5-6 membered monocyclicheteroaromatic ring or a benzene ring, thereby forming a 8-11 memberedbicyclic heteroaryl ring; wherein any one or more of the rings presentin R¹⁰ is independently optionally substituted with one or more R¹³;each R¹³ is independently selected from the group consisting of halogen,cyano, oxo, epoxy and a group-L¹-X¹-Q¹ wherein: L¹ is absent or (1-3C)alkylene; X¹ is absent or isselected from the group consisting of —O—, —C(O)—, —C(O)—O—, —O—C(O)—,—S(O)₀₋₂—, —C(O)—N(R¹⁴)—, —N(R¹⁴)—C(O)—, —NR¹⁴—, —N(R¹⁴)—C(O)—NR¹⁴—,—SO₂N(R¹)—, or —N(R¹⁴)SO₂—, where R¹⁴ is, at each occurrence,independently selected from the group consisting of hydrogen, hydroxy,cyano, (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl, where any(1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl in R¹⁴ is independentlyoptionally substituted with one or more groups selected from the groupconsisting of halogen and hydroxy; Q¹ is selected from the groupconsisting of hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(3-8C)cycloalkyl, (3-8C)cycloalkyl(1-3C)alkyl, aryl, aryl(1-3C)alkyl,heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl andheteroaryl(1-3C)alkyl, wherein any (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-3C)alkyl, aryl,aryl(1-3C)alkyl, heterocyclyl, heterocyclyl(1-3C)alkyl, heteroaryl orheteroaryl(1-3C)alkyl in Q¹ is optionally substituted with one or moregroups R¹⁵; and each R¹⁵ is independently selected from the groupconsisting of hydroxy, cyano, oxo, halogen, (1-3C)alkyl, (1-3C)alkoxy,—NR^(15a)R^(15b), —C(O)—R^(15a), —C(O)—OR^(15a), —O—C(O)—R^(15a),—C(O)—NR^(15a)R^(15b), —N(R^(15b))C(O)—R^(15a), —S(O)₀₋₂R^(15a),—S(O)₂NR^(15a)R^(15b), and —N(R^(15b))—S(O)₂R^(15a), wherein R^(15a) andR^(15b) are each independently hydrogen or (1-3C)alkyl, and wherein any(1-3C)alkyl moiety present in a R^(15a) or R^(15b) group is optionallyfurther substituted by one or more substituents independently selectedfrom hydroxy, cyano, halogen, —OR^(15c), —NR^(15c)R^(15d) and—C(O)—R^(15c), wherein R^(15c) and R^(15d) are both independentlyselected from hydrogen and (1-2C)alkyl.
 2. The compound, orpharmaceutically acceptable salts, hydrates or solvates thereof,according to claim 1, wherein R¹ and R³ are independently selected fromthe group consisting of hydrogen, hydroxy, fluoro and methoxy, with theproviso that at least one of R¹ and R³ is hydroxy.
 3. The compound, orpharmaceutically acceptable salts, hydrates or solvates thereof,according to claim 1 or 2, wherein R¹ and R³ are both hydroxy.
 4. Thecompound, or pharmaceutically acceptable salts, hydrates or solvatesthereof, according to claim 1, 2 or 3, wherein R² is hydrogen; and R⁴ isselected from the group consisting of hydrogen, fluoro, chloro(1-4C)alkyl, cyclopropyl and cyclobutyl, wherein the said (1-4C)alkyl isoptionally substituted by one R^(5a) and the said cyclopropyl andcyclobutyl groups are optionally substituted with one R^(5b).
 5. Thecompound, or pharmaceutically acceptable salts, hydrates or solvatesthereof, according to any preceding claim, wherein R⁷ is hydrogen ormethyl; and n is
 1. 6. The compound, or pharmaceutically acceptablesalts, hydrates or solvates thereof, according to any preceding claim,wherein R⁸ is phenyl or 5-6 membered heteroaryl containing 1, 2 or 3ring heteroatoms independently selected from N and O, wherein the saidphenyl or 5-6 membered heteroaryl is optionally substituted with one,two or three R⁹.
 7. The compound, or pharmaceutically acceptable salts,hydrates or solvates thereof, according to any preceding claim, whereinR⁸ has any one of the following structures:

wherein each m¹ is independently 0, 1, 2 or 3; and each m² isindependently 0, 1 or
 2. 8. The compound, or pharmaceutically acceptablesalts, hydrates or solvates thereof, according to any preceding claim,wherein R³ has the following structure:

wherein m¹ is 0, 1, 2 or
 3. 9. The compound, or pharmaceuticallyacceptable salts, hydrates or solvates thereof, according to anypreceding claim, wherein each R⁹ is independently selected from thegroup consisting of hydroxy, halogen, (1-3C)alkyl, (1-3C)alkoxy,(2-3C)alkenyl and (2-3C)alkynyl.
 10. The compound, or pharmaceuticallyacceptable salts, hydrates or solvates thereof, according to anypreceding claim, wherein R¹¹ and R¹² are linked, such that, togetherwith the nitrogen atom to which they are attached, they form any one ofthe following ring systems:

wherein v² and v³ are each independently 1 or 2; W¹ is CH, N or O; eachring A is a benzene ring or a 5-6 membered heteroaromatic ring; and anyring is optionally substituted with one or two R¹³.
 11. The compound, orpharmaceutically acceptable salts, hydrates or solvates thereof,according to any preceding claim, wherein R¹¹ and R¹² are linked, suchthat, together with the nitrogen atom to which they are attached, theyform any one of the following ring systems:

wherein v¹ is 1, 2 or 3; v² and v³ are each independently 1 or 2; W¹ isCH, N or O; each ring A is a benzene ring or a 5-6 memberedheteroaromatic ring containing 1, 2 or 3 N atoms; each R^(13a) isindependently selected from the group consisting of oxo, hydroxy, halo,(1-3C)alkyl and (1-3C)alkoxy, wherein any (1-3C)alkyl and (1-3C)alkoxyin R^(13a) is optionally substituted with one or more groupsindependently selected from the group consisting of hydroxy and halo;each q² is independently 0, 1 or 2; and each q³ is independently 0 or 1.12. The compound, or pharmaceutically acceptable salts, hydrates orsolvates thereof, according to any one of claims 1-10, wherein R¹¹ andR¹² are linked, such that, together with the nitrogen atom to which theyare attached, they form any one of the following ring systems:

wherein each q² is independently 0 or 1; each q³ is independently 0, 1or 2; v² and v³ are each independently 1 or 2; W³ and W⁴ are eachindependently OH, N or O, providing that only zero, one or two of W², W³and W⁴ are N or O; W⁵, W⁶, W⁷ and W⁸ are each independently CH, N or O,providing that only zero, one or two of W⁵, W⁶, W⁷ and W⁸ are N or O; W⁹is N, O or CH₂ W¹⁰ is C or N; W¹¹, W¹² and W¹³ are each independentlyCH, N or O, providing that only zero, one or two of W¹¹, W¹² and W¹³ areN or O; W¹⁴, W¹⁵, W¹⁶ and W¹⁷ are each independently CH, N or O,providing that only zero, one or two of W¹⁴, W¹⁵, W¹⁶ and W¹⁷ are N orO; W¹⁸ is N, O or CH₂ W¹⁹ is C or N; and W²⁰, W²¹, W²² and W²³ are eachindependently CH, N or O, providing that only zero, one or two of W²⁰,W²¹, W²² and W²³ are N or O.
 13. The compound, or pharmaceuticallyacceptable salts, hydrates or solvates thereof, according to claim 12,wherein W², W³ and W⁴ are each independently CH or N, providing thatonly zero, one or two of W², W³ and W⁴ are N; W⁵, W⁶, W⁷ and W⁸ are eachindependently CH or N, providing that only zero, one or two of W⁵, W⁶,W⁷ and W⁸ are N; W¹¹, W¹² and W¹³ are each independently CH or N,providing that only zero, one or two of W¹¹, W¹² and W¹³ are N; W¹⁴,W¹⁵, W¹⁶ and W¹⁷ are each independently CH or N, providing that onlyzero, one or two of W¹⁴, W¹⁵, W¹⁶ and W¹⁷ are N; and W²⁰, W²¹, W²² andW²³ are each independently CH or N, providing that only zero, one or twoof W²⁰, W²¹, W²² and W²³ are N.
 14. The compound, or pharmaceuticallyacceptable salts, hydrates or solvates thereof, according to anypreceding claim, wherein R¹¹ and R¹² are linked, such that, togetherwith the nitrogen atom to which they are attached, they form any one ofthe following ring systems:

wherein each q² is independently 0 or 1 and each q³ is independently 0,1 or 2; and each R^(13a) is independently selected from the groupconsisting of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, whereinany (1-3C)alkyl and (1-3C)alkoxy in R^(13a) is optionally substitutedwith one or more groups independently selected from the group consistingof hydroxy and halo.
 15. The compound, or pharmaceutically acceptablesalts, hydrates or solvates thereof, according to any one of claims1-11, wherein R¹¹ and R¹² are linked, such that, together with thenitrogen atom to which they are attached, they form the following ringsystem:

wherein v² is 1 or 2; ring A is a benzene ring or a 5-6 memberedheteroaromatic ring containing 1, 2 or 3 heteroatoms independentlyselected from N and 0; each R^(13a) is independently selected from thegroup consisting of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy,wherein any (1-3C)alkyl and (1-3C)alkoxy in R^(13a) is optionallysubstituted with one or more groups independently selected from thegroup consisting of hydroxy and halo; each q² is independently 0, 1 or2; and each q³ is independently 0 or
 1. 16. The compound, orpharmaceutically acceptable salts, hydrates or solvates thereof,according to any one of claims 1-11, wherein R¹¹ and R¹² are linked,such that, together with the nitrogen atom to which they are attached,they form any one of the following ring systems:

wherein each q² is independently 0 or 1 and each q³ is independently 0,1 or 2; and each R^(13a) is independently selected from the groupconsisting of oxo, hydroxy, halo, (1-3C)alkyl and (1-3C)alkoxy, whereinany (1-3C)alkyl and (1-3C)alkoxy in R^(13a) is optionally substitutedwith one or more groups independently selected from the group consistingof hydroxy and halo.
 17. The compound, or pharmaceutically acceptablesalts, hydrates or solvates thereof, according to any preceding claim,wherein each R¹³ is independently selected from the group consisting ofhalogen, oxo, epoxy and a group -L¹-X¹-Q¹.
 18. The compound, orpharmaceutically acceptable salts, hydrates or solvates thereof,according to any preceding claim, wherein L¹ is absent or(1-2C)alkylene; X¹ is absent or is selected from the group consisting of—O—, —C(O)—, —C(O)—O—, —O—C(O)—, —S(O)₀₋₂—, —C(O)—N(R¹⁴)—,—N(R¹⁴)—C(O)—, or —NR¹⁴—, where R¹⁴ is, at each occurrence,independently selected from the group consisting of hydrogen, hydroxy,cyano, (1-4C)alkyl and (2-4C)alkenyl, where any (1-4C)alkyl or(2-4C)alkenyl in R¹⁴ is independently optionally substituted with one ormore groups selected from the group consisting of halogen and hydroxy;and Q¹ is selected from the group consisting of hydrogen, (1-6C)alkyl,(2-6C)alkenyl, aryl, heterocyclyl and heteroaryl, wherein any(1-6C)alkyl, (2-6C)alkenyl, aryl, heterocyclyl or heteroaryl in Q¹ isoptionally substituted with one or more groups R¹⁵.
 19. The compound, orpharmaceutically acceptable salts, hydrates or solvates thereof,according to any preceding claim, wherein L¹ is absent or(1-2C)alkylene; X¹ is absent or is selected from the group consisting of—O—, —C(O)—, —C(O)—O—, —N(R¹⁴)—C(O)—, or —NR¹⁴—, where R¹⁴ is, at eachoccurrence, independently selected from the group consisting ofhydrogen, cyano, (1-4C)alkyl and (2-4C)alkenyl; and Q¹ is selected fromthe group consisting of hydrogen, (1-4C)alkyl, (2-4C)alkenyl, phenyl,5-6 membered heterocyclyl containing 1 or 2 heteroatoms independentlyselected from N and O, and 5-6 membered heteroaryl containing 1 or 2heteroatoms independently selected from N and O, wherein any(1-4C)alkyl, (2-4C)alkenyl, phenyl, 5-6 membered heterocyclyl or 5-6membered heteroaryl in Q¹ is optionally substituted with one, two orthree groups R¹⁵.
 20. The compound, or pharmaceutically acceptablesalts, hydrates or solvates thereof, according to any preceding claim,wherein each R¹⁵ is independently selected from the group consisting ofhydroxy, cyano, halogen, (1-3C)alkyl, (1-3C)alkoxy, —NR^(15a)R^(15b) and—C(O)—NR^(15a)R^(15b), wherein R^(15a) and R^(15b) are eachindependently hydrogen or (1-3C)alkyl.
 21. The compound, orpharmaceutically acceptable salts, hydrates or solvates thereof,according to any preceding claim, wherein each R¹⁵ is independentlyselected from the group consisting of hydroxy, halogen, (1-3C)alkyl and—C(O)—NR^(15a)R^(15b), wherein R^(15a) and R^(15b) are eachindependently hydrogen or methyl.
 22. The compound, or pharmaceuticallyacceptable salts, hydrates or solvates thereof, according to anypreceding claim, wherein the compound is selected from any one of thefollowing:[2,4-dihydroxy-6-(pyrimidin-2-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;[2-(cyclopentoxy)-4,6-dihydroxy-phenyl]-pyrrolidin-1-yl-methanone;(2-benzyloxy-4,6-dihydroxy-phenyl)-pyrrolidin-1-yl-methanone;(2-benzyloxy-4,6-dihydroxy-phenyl)-isoindolin-2-yl-methanone;(2-benzyloxy-4,6-dihydroxy-phenyl)-(1-piperidyl)methanone;(2-benzyloxy-4,6-dihydroxy-phenyl)-[(3S)-3-hydroxypyrrolidin-1-yl]methanone;(2-benzyloxy-4,6-dihydroxy-phenyl)-[(3R)-3-hydroxypyrrolidin-1-yl]methanone;(2-benzyloxy-4,6-dihydroxy-phenyl)-[(3R)-3-hydroxy-1-piperidyl]methanone;(2-benzyloxy-4,6-dihydroxy-phenyl)-[(3S)-3-hydroxy-1-piperidyl]methanone;(2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-pyrrolidin-1-yl-methanone;(2-benzyloxy-3-ethyl-4,6-dihydroxy-phenyl)-pyrrolidin-1-yl-methanone;[2,4-dihydroxy-6-(2-pyridylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;[2,4-dihydroxy-6-[(1R)-1-phenylethoxy]phenyl]-pyrrolidin-1-yl-methanone;[2,4-dihydroxy-6-[(1R)-1-phenylethoxy]phenyl]-pyrrolidin-1-yl-methanone;[2-[(4-fluorophenyl)methoxy]-4,6-dihydroxy-phenyl]-pyrrolidin-1-yl-methanone;[2,4-dihydroxy-6-[(4-methoxyphenyl)methoxy]phenyl]-pyrrolidin-1-yl-methanone;[2,4-dihydroxy-6-(m-tolylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;(2-benzyloxy-4,6-dihydroxy-phenyl)-(5,7-dihydropyrrolo[3,4-b]pyridin-6-yl)methanone;(2-benzyloxy-4,6-dihydroxy-phenyl)-(4-methoxyisoindolin-2-yl)methanone;[2,4-dihydroxy-6-(pyrimidin-4-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;2,4-dihydroxy-6-(1H-pyrazol-3-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;[2,4-dihydroxy-6-(1H-triazol-4-ylmethoxy)phenyl]-pyrrolidin-1-yl-methanone;(2-benzyloxy-4,6-dihydroxy-phenyl)-(5-bromoisoindolin-2-yl)methanone;methyl 2-(2-benzyloxy-4,6-dihydroxy-benzoyl)isoindoline-5-carboxylate;(2-benzyloxy-4,6-dihydroxy-phenyl)-(5-methoxyisoindolin-2-yl)methanone;(2-benzyloxy-4,6-dihydroxy-phenyl)-(5,6-dimethoxyisoindolin-2-yl)methanone;[2,4-dihydroxy-6-(1-phenylethoxy)phenyl]-isoindolin-2-yl-methanone;[2,4-dihydroxy-6-(1-phenylethoxy)phenyl]-(5-methoxyisoindolin-2-yl)methanone;[2,4-dihydroxy-6-(1-phenylethoxy)phenyl]-(5,6-dimethoxyisoindolin-2-yl)methanone;(2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(5,7-dihydropyrrolo[3,4-b]pyridin-6-yl)methanone;5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[4,6-dihydroxy-3-methyl-2-(m-tolylmethoxy)phenyl]methanone;5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[2,4-dihydroxy-6-(m-tolylmethoxy)phenyl]methanone;5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]methanone;[4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-isoindolin-2-yl-methanone;5,7-dihydropyrrolo[3,4-b]pyridin-6-yl-[2,4-dihydroxy-6-(2-pyridylmethoxy)phenyl]methanone;(2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-isoquinolin-2-yl)methanone;[2,4-dihydroxy-6-(2-pyridylmethoxy)phenyl]-isoindolin-2-yl-methanone;(2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(4-bromoisoindolin-2-yl)methanone;(2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-[4-(hydroxymethyl)isoindolin-2-yl]methanone;(2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-[5-[(4-methylpiperazin-1-yl)methyl]isoindolin-2-yl]methanone;(2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone;(2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)methanone;(2-benzyloxy-4,6-dihydroxy-3-methyl-phenyl)-(3,4-dihydro-1H-2,6-naphthyridin-2-yl)methanone;3,4-dihydro-1H-isoquinolin-2-yl-[4,6-dihydroxy-3-methyl-2-(m-tolylmethoxy)phenyl]methanone;3,4-dihydro-1H-isoquinolin-2-yl-[4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]methanone;[4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone;[4,6-dihydroxy-3-methyl-2-(2-pyridylmethoxy)phenyl]-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)methanone;3,4-dihydro-1H-isoquinolin-2-yl-[2-[(4-fluorophenyl)methoxy]-4,6-dihydroxy-3-methyl-phenyl]methanone;(2-(benzyloxy)-4,6-dihydroxyphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;(4-aminoisoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)methanone;(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-vinylisoindolin-2-yl)methanone;(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methanone;(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methanone;(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone;(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methanone;(3,4-dihydroisoquinolin-2(1H)-yl)(4,6-dihydroxy-3-methyl-2-((1-methyl-1H-pyrazol-3-yl)methoxy)phenyl)methanone;(2-(benzyloxy)-4,6-dihydroxyphenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone;(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(isoindolin-2-yl)methanone;(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(7-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;(S)-(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1-(hydroxymethyl)isoindolin-2-yl)methanone;(R)-(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5-((dimethylamino)methyl)isoindolin-2-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(5-(morpholinomethyl)isoindolin-2-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(indolin-1-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxyphenyl)(indolin-1-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(3,4-dihydroquinolin-1(2H)-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxyphenyl)(3,4-dihydroquinolin-1(2H)-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(morpholinomethyl)isoindolin-2-yl)methanone;2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxamide;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)amino)isoindolin-2-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(oxetan-3-ylamino)isoindolin-2-yl)methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(3-hydroxypiperidin-1-yl)isoindolin-2-yl)methanone;2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindoline-4-carbonitrile;2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-5-carboxamide;2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-methylisoindoline-5-carboxamide;2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N,N-dimethylisoindoline-4-carboxamide;2-(2-(benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)-N-methylisoindoline-4-carboxamide;N-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)acetamide;((2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-((tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)methanone;(4-(Azetidin-3-yl methoxy) isoindolin-2-yl)(2-(benzyloxy)-4,6-dihydroxy-3-methylphenyl) methanone;(2-(Benzyloxy)-4,6-dihydroxy-3-methylphenyl)(4-(pyrimidin-5-ylmethoxy)isoindolin-2-yl)methanone;1-(2-(2-(Benzyloxy)-4,6-dihydroxy-3-methylbenzoyl)isoindolin-4-yl)azetidine-3-carbonitrile;(4,6-Dihydroxy-2-methoxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;(2-Ethoxy-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;(2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;(2-(Cyclopropylmethoxy)-4,6-dihydroxy-3-methylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone;and(2-(Cyclohexylmethoxy)-4,6-dihydroxy-3-methylphenyl)(6-((dimethylamino)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone.23. A pharmaceutical composition comprising a compound as defined in anypreceding claim, or a pharmaceutically acceptable salt, hydrate orsolvate thereof, in admixture with a pharmaceutically acceptable diluentor carrier.
 24. A method of treating a proliferative disorder in apatient in need of such treatment, said method comprising administeringto said patient a therapeutically effective amount of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, as definedin any one of claims 1-22, or a pharmaceutical composition as defined inclaim
 23. 25. A compound, or a pharmaceutically acceptable salt, hydrateor solvate thereof, as defined in any one of claims 1-22, or apharmaceutical composition as defined in claim 23, for use in therapy.26. A compound, or a pharmaceutically acceptable salt, hydrate orsolvate thereof, as defined in any one of claims 1-22, or apharmaceutical composition as defined in claim 23, for use in: (i) thetreatment of cancer; (ii) the treatment of cancer, wherein the compoundor pharmaceutical composition is administered in combination withanother anticancer agent (e.g. a chemotherapeutic agent, an immunecheckpoint inhibitor, an immune stimulator or DNA damage repairmodulator); (ii) the treatment of a triplet repeat disorder.